Panic DisorderNCT00103987
Neurobiological Mechanisms in Panic Disorder
An observational study of Panic Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial summary
This study will examine brain and noradrenaline function in panic disorder. Noradrenaline is a brain chemical that is involved in the regulation of emotion, anxiety, sleep, stress hormones such as cortisol, and other body functions that are disturbed in panic disorder. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Panic Disorder
- How many people
- 54 participants
- Where
- 1 siteUnited States
- Study dates
- 14 Feb 2005to 12 Nov 2010
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Up to 120 drug-free subjects (ages 18-60) will be selected who additionally meet criteria for one of 3 subgroups:
- PD, current (n=30), as defined by DSM-IV criteria for PD, and still symptomatic as defined by at least 1 panic attack/week or a CGI score of at least 4. In case of co-morbid depression it will be ensured that PD is the primary diagnosis. This means that PD preceded the onset of MDD. These patients will be drug-free for at least 2 weeks prior to being enrolled in the study.
- PD, remitted (n=30), as defined by DSM-IV criteria for PD, and asymptomatic as no longer meeting criteria for PD while being drug-free during the past 6 months.
- Healthy Control Sample. Sixty subjects (ages 18-60) who have not met criteria for any major psychiatric disorder (axis I diagnosis according to DSM-IV). A control subject will be matched to each PD subject for age, gender, menopausal and estrogen replacement status, and handedness. The control subjects will have no known first-degree relatives with any axis I disorder.
Who cannot join
- Symptomatic PD patients must not have taken any antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular and cardiovascular function for at least 2 weeks prior to the challenge studies.
- Remitted PD patients will be drug-free for at least 6 months prior to enrollment.
- Subjects will also be excluded if they have:
- evidence for an axis I psychiatric disorder (DSM-IV criteria) other than panic disorder with/without agoraphobia with/without comorbid depression,
- medical or neurological illnesses likely to affect physiology or anatomy, i.e. hypertension, cardiovascular disorders, seizures,
- a history of drug (including BZDs) or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria),
Show all 13Show fewer
- current pregnancy (as documented by pregnancy testing at screening or on the days of the challenge studies),
- current breast feeding,
- are smokers,
- presence of an axis II personality disorder,
- current treatment with fluoxetine, or
- history of an adverse reaction associated with the administration of yohimbine.
- Subjects beyond age 60 are excluded.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Neurobiological Mechanisms in Panic Disorder: Behavioral, Genetic, & Neural Correlates of Noradrenergic Function
This study will examine brain and noradrenaline function in panic disorder. Noradrenaline is a brain chemical that is involved in the regulation of emotion, anxiety, sleep, stress hormones such as cortisol, and other body functions that are disturbed in panic disorder.
Healthy normal volunteers and patients with panic disorder between 18 and 60 years of age may be eligible for this study. Candidates are screened with psychiatric and medical histories, a physical examination, blood and urine tests, and an electrocardiogram.
Read more
Participants undergo the following tests and procedures:
- Blood draw to obtain DNA for genetic studies of panic disorder - particularly of a gene that helps control noradrenaline activity - and to grow cell lines that can be frozen and used for future research on the disorder.
- Magnetic resonance imaging: MRI uses a magnetic field and radio waves to produce images of body tissues and organs. For this procedure, the subject lies on a table that is moved into the scanner (a narrow cylinder), and wears earplugs to muffle loud knocking and thumping sounds that occur during the scanning process. The procedure lasts about 60 minutes, during which the patient is asked to lie still for 10 to 15 minutes at a time.
- Yohimbine injection with PET scanning: Catheters (plastic tubes) are placed in two veins, one to administer yohimbine, a drug that increases noradrenaline activity in the body for about 60 minutes, and one to draw blood samples. Yohimbine often causes temporary trembling, goosebumps, and clammy palms, and may cause emotions such as elation, anxiety, panic attacks, or depression. During yohimbine administration, subjects undergo positron emission tomography (PET) scanning. PET uses small amounts of a radioactive chemical called [fluoro-18]-fluorodeoxyglucose that "labels" active areas of the brain, showing patterns of glucose (sugar) metabolism. For the procedure, the subject lies on the scanner bed, with a special mask fitted to his or her head and attached to the bed to help keep the head still. A brief "transmission" scan is done just before the radioactive tracer is injected in order to calibrate the scanner. After the tracer is injected through the catheter, pictures are taken for about an hour, while the subject lies still on the scanner bed.
- Saline injection with PET scanning: The procedure is the same as that described above, except a saline solution is administered as placebo instead of yohimbine.
Read the detailed description
A considerable body of preclinical and clinical evidence suggests that dysregulated activity of noradrenergic systems in the brain is involved in the development of mood disturbance, anxiety, and fear. Neuroanatomical and neurophysiological studies of the noradrenergic system provide a basis for relating increased activity of this system to the behavioral expression of fear and anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states. Previously, extensive research has been done on the role of noradrenergic mechanisms in panic disorder (PD), and it has been suggested that in at least a subgroup of PD patients an abnormality of noradrenergic mechanisms may exist. Studies in patients with PD using the alpha2-adrenoreceptor (AR) antagonist yohimbine showed that a subgroup of PD patients exhibit abnormalities in the regulation of noradrenergic function. Yohimbine, which activates noradrenergic neurons, has been shown to produce greater increases in anxiety, somatic symptoms, blood pressure and plasma levels of the noradrenergic metabolite MHPG in some patients with PD relative to healthy controls. The effect of yohimbine on brain regions hypothesized to be involved in the pathogenesis of PD has not been determined in PD patients using modern neuroimaging techniques. The anxiogenic effects of yohimbine do not occur in all PD patients, although the neurobiological basis for this differential response to yohimbine has not been identified.
This research project proposes to address these two unresolved questions. The effects of yohimbine on regional cerebral glucose metabolism will be determined in PD patients and healthy controls. In addition, preliminary data will be obtained as to whether the behavioral and cerebral metabolic responses to yohimbine relate to functional polymorphisms of the COMT gene which affect catecholamine metabolism.
It is predicted that yohimbine will produce decreases in cerebral metabolism in the prefrontal cortex, orbitofrontal cortex, and anterior cingulate. Healthy controls will exhibit an inverse direction of change in these brain regions. These findings would be similar to those we have previously observed in PTSD patients and may reflect an altered dose-response effect of yohimbine in PD and PTSD relative to controls since preclinical pharmacological studies of stress have shown that high levels of norepinephrine release in the brain decrease brain metabolism whereas lower levels increase brain metabolism. In terms of polymorphisms of the COMT and other catecholamine systems-related gene polymorphisms, it is predicted that the low-activity COMT (met allele) alleles will be associated with greater behavioral and cerebral metabolic responses to yohimbine.
- Conditions
- Panic Disorder
- Keywords
- Panic Disorder, Norepinephrine, Yohimbine, Genes, Pathophysiology, Noradrenergic Mechanisms, PET Imaging, PD, Healthy Volunteer, HV
- Medical subject headings
- Panic Disorder
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Feb 2005 (estimated)
- Study start14 Feb 2005
- Study completion12 Nov 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Panic DisorderStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00103987
- Sponsor's protocol ID
- 050102
- Other IDs
- 05-M-0102
- Status last verified
- 12 Nov 2010
- First submitted
- 17 Feb 2005
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Bisaga A, Katz JL, Antonini A, Wright CE, Margouleff C, Gorman JM, Eidelberg D. Cerebral glucose metabolism in women with panic disorder. Am J Psychiatry. 1998 Sep;155(9):1178-83. doi: 10.1176/ajp.155.9.1178.
PubMed 9734539Cameron OG, Zubieta JK, Grunhaus L, Minoshima S. Effects of yohimbine on cerebral blood flow, symptoms, and physiological functions in humans. Psychosom Med. 2000 Jul-Aug;62(4):549-59. doi: 10.1097/00006842-200007000-00014.
PubMed 10949101Schmidt ME, Oshinsky RJ, Kim HG, Schouten JL, Folley BS, Potter WZ. Cerebral glucose metabolic and plasma catecholamine responses to the alpha(2) adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers. Psychopharmacology (Berl). 1999 Sep;146(2):119-27. doi: 10.1007/s002130051097.
PubMed 10525746
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neurobiological Mechanisms in Panic Disorder: Behavioral, Genetic, & Neural Correlates of Noradrenergic Function
- ClinicalTrials.gov ID
- NCT00103987
- Acronym / sponsor ID
- 050102
- Conditions
- Panic Disorder
- Keywords
- Panic Disorder, Norepinephrine, Yohimbine, Genes, Pathophysiology, Noradrenergic Mechanisms, PET Imaging, PD
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 54 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- 14 Feb 2005
- Study completion
- 12 Nov 2010
- First posted
- 18 Feb 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will examine brain and noradrenaline function in panic disorder. Noradrenaline is a brain chemical that is involved in the regulation of emotion, anxiety, sleep, stress hormones such as cortisol, and other body functions that are disturbed in panic disorder.
Healthy normal volunteers and patients with panic disorder between 18 and 60 years of age may be eligible for this study. Candidates are screened with psychiatric and medical histories, a physical examination, blood and urine tests, and an electrocardiogram.
Participants undergo the following tests and procedures:
- Blood draw to obtain DNA for genetic studies of panic disorder - particularly of a gene that helps control noradrenaline activity - and to grow cell lines that can be frozen and used for future research on the disorder.
- Magnetic resonance imaging: MRI uses a magnetic field and radio waves to produce images of body tissues and organs. For this procedure, the subject lies on a table that is moved into the scanner (a narrow cylinder), and wears earplugs to muffle loud knocking and thumping sounds that occur during the scanning process. The procedure lasts about 60 minutes, during which the patient is asked to lie still for 10 to 15 minutes at a time.
- Yohimbine injection with PET scanning: Catheters (plastic tubes) are placed in two veins, one to administer yohimbine, a drug that increases noradrenaline activity in the body for about 60 minutes, and one to draw blood samples. Yohimbine often causes temporary trembling, goosebumps, and clammy palms, and may cause emotions such as elation, anxiety, panic attacks, or depression. During yohimbine administration, subjects undergo positron emission tomography (PET) scanning. PET uses small amounts of a radioactive chemical called [fluoro-18]-fluorodeoxyglucose that "labels" active areas of the brain, showing patterns of glucose (sugar) metabolism. For the procedure, the subject lies on the scanner bed, with a special mask fitted to his or her head and attached to the bed to help keep the head still. A brief "transmission" scan is done just before the radioactive tracer is injected in order to calibrate the scanner. After the tracer is injected through the catheter, pictures are taken for about an hour, while the subject lies still on the scanner bed.
- Saline injection with PET scanning: The procedure is the same as that described above, except a saline solution is administered as placebo instead of yohimbine.
Detailed description
A considerable body of preclinical and clinical evidence suggests that dysregulated activity of noradrenergic systems in the brain is involved in the development of mood disturbance, anxiety, and fear. Neuroanatomical and neurophysiological studies of the noradrenergic system provide a basis for relating increased activity of this system to the behavioral expression of fear and anxiety and the somatic symptoms and cardiovascular changes that accompany severe anxiety states. Previously, extensive research has been done on the role of noradrenergic mechanisms in panic disorder (PD), and it has been suggested that in at least a subgroup of PD patients an abnormality of noradrenergic mechanisms may exist. Studies in patients with PD using the alpha2-adrenoreceptor (AR) antagonist yohimbine showed that a subgroup of PD patients exhibit abnormalities in the regulation of noradrenergic function. Yohimbine, which activates noradrenergic neurons, has been shown to produce greater increases in anxiety, somatic symptoms, blood pressure and plasma levels of the noradrenergic metabolite MHPG in some patients with PD relative to healthy controls. The effect of yohimbine on brain regions hypothesized to be involved in the pathogenesis of PD has not been determined in PD patients using modern neuroimaging techniques. The anxiogenic effects of yohimbine do not occur in all PD patients, although the neurobiological basis for this differential response to yohimbine has not been identified.
This research project proposes to address these two unresolved questions. The effects of yohimbine on regional cerebral glucose metabolism will be determined in PD patients and healthy controls. In addition, preliminary data will be obtained as to whether the behavioral and cerebral metabolic responses to yohimbine relate to functional polymorphisms of the COMT gene which affect catecholamine metabolism.
It is predicted that yohimbine will produce decreases in cerebral metabolism in the prefrontal cortex, orbitofrontal cortex, and anterior cingulate. Healthy controls will exhibit an inverse direction of change in these brain regions. These findings would be similar to those we have previously observed in PTSD patients and may reflect an altered dose-response effect of yohimbine in PD and PTSD relative to controls since preclinical pharmacological studies of stress have shown that high levels of norepinephrine release in the brain decrease brain metabolism whereas lower levels increase brain metabolism. In terms of polymorphisms of the COMT and other catecholamine systems-related gene polymorphisms, it is predicted that the low-activity COMT (met allele) alleles will be associated with greater behavioral and cerebral metabolic responses to yohimbine.
Study design
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Up to 120 drug-free subjects (ages 18-60) will be selected who additionally meet criteria for one of 3 subgroups:
- PD, current (n=30), as defined by DSM-IV criteria for PD, and still symptomatic as defined by at least 1 panic attack/week or a CGI score of at least 4. In case of co-morbid depression it will be ensured that PD is the primary diagnosis. This means that PD preceded the onset of MDD. These patients will be drug-free for at least 2 weeks prior to being enrolled in the study.
- PD, remitted (n=30), as defined by DSM-IV criteria for PD, and asymptomatic as no longer meeting criteria for PD while being drug-free during the past 6 months.
- Healthy Control Sample. Sixty subjects (ages 18-60) who have not met criteria for any major psychiatric disorder (axis I diagnosis according to DSM-IV). A control subject will be matched to each PD subject for age, gender, menopausal and estrogen replacement status, and handedness. The control subjects will have no known first-degree relatives with any axis I disorder.
Key exclusion criteria (13 listed)
- Symptomatic PD patients must not have taken any antidepressant or other medications likely to alter monoamine neurochemistry or cerebrovascular and cardiovascular function for at least 2 weeks prior to the challenge studies.
- Remitted PD patients will be drug-free for at least 6 months prior to enrollment.
- evidence for an axis I psychiatric disorder (DSM-IV criteria) other than panic disorder with/without agoraphobia with/without comorbid depression,
- medical or neurological illnesses likely to affect physiology or anatomy, i.e. hypertension, cardiovascular disorders, seizures,
- a history of drug (including BZDs) or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria),
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 9734539Bisaga A, Katz JL, Antonini A, Wright CE, Margouleff C, Gorman JM, Eidelberg D. Cerebral glucose metabolism in women with panic disorder. Am J Psychiatry. 1998 Sep;155(9):1178-83. doi: 10.1176/ajp.155.9.1178.
- Background: PubMed 10949101Cameron OG, Zubieta JK, Grunhaus L, Minoshima S. Effects of yohimbine on cerebral blood flow, symptoms, and physiological functions in humans. Psychosom Med. 2000 Jul-Aug;62(4):549-59. doi: 10.1097/00006842-200007000-00014.
- Background: PubMed 10525746Schmidt ME, Oshinsky RJ, Kim HG, Schouten JL, Folley BS, Potter WZ. Cerebral glucose metabolic and plasma catecholamine responses to the alpha(2) adrenoceptor antagonist ethoxyidazoxan given to healthy volunteers. Psychopharmacology (Berl). 1999 Sep;146(2):119-27. doi: 10.1007/s002130051097.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Panic Disorder, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00103987, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.