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Genetic Causes of Panic Disorder

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00083265
Recruitment Status : Completed
First Posted : May 17, 2004
Last Update Posted : February 16, 2018
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )

Brief Summary:

This study will try to identify genes that increase the risk of developing panic disorder-an anxiety disorder characterized by recurrent unexpected panic attacks-and that contribute to the abnormalities associated with it. It will compare reactions in patients with panic disorder and in normal volunteers to caffeine, a compound that can induce anxiety, and to placebo, an inactive substance. Caffeine is believed to induce anxiety by blocking proteins called adenosine receptors on the surface of nerve cells in the brain. One study found that people with a specific adenosine receptor gene called 1976T/T had greater anxiety in response to caffeine challenge than did people with other adenosine receptor gene groups. There is also evidence that people with the 1976T/T genotype are more vulnerable to having panic disorder.

Normal volunteers and patients with panic disorder (with or without agoraphobia) who are between 18 and 60 years of age may be eligible for this study. Candidates are screened with physical and psychiatric examinations, a diagnostic interview, mood and anxiety ratings, an electrocardiogram, and blood and urine tests, including genetic studies.

Participants have two caffeine/placebo challenge sessions at least 3 days apart. Each session lasts about 4 hours. For at least 1 week before each session, subjects follow a diet excluding foods with caffeine and refrain from drinking alcoholic beverages for at least 48 hours before the procedure. The morning of the session, following an overnight fast, subjects swallow either a placebo capsule or a caffeine capsule that is equivalent to about 5 cups of coffee. During the session, subjects take a battery of neuropsychological tests to document changes in cognitive and emotional functioning, including attention, memory, and motor performance. In addition, heart rate and blood pressure are measured 15 minutes before and 30, 60, 90, 120, 150, and 180 minutes after the caffeine or placebo dose.

At the end of the study, patients with panic disorder are eligible to receive routine clinical treatment for up to 3 months and may participate in planning for long-term treatment under the care of their local health care provider.


Condition or disease
Panic Disorder

Detailed Description:

Caffeine, the most widely used psychoactive drug in the world, exerts its behavioral effects by antagonizing adenosine receptors (AR). Four different human AR subtypes have been found and there is evidence that the stimulatory effect of caffeine is mainly caused by an inhibition of transmission via adenosine A(2a) receptors. A significant association has been found in healthy infrequent caffeine users between caffeine-induced anxiety and two linked polymorphisms on the A(2a) receptor gene, the 1976C greater than T and 2592C greater than Tins polymorphisms. In one study looking at monozygotic and dizygotic twin pairs, there was much evidence that individual differences in caffeine use, intoxication, tolerance, and withdrawal were substantially influenced by genetic factors. Family and twin studies have shown that genetic factors may increase vulnerability to panic disorder. In one study a systematic mutation screening and association study of the A(1) and A(2a) adenosine receptor genes in panic disorder showed a significant association between the 1976T allele and 1976T/T genotype of the A(2a) receptor gene and panic disorder. As the 1976T/T genotype of the A(2a) receptor gene has been associated with both increased caffeine-induced anxiety in healthy controls, and has been associated with increased vulnerability to panic disorder, we wish to study whether the 1976T/T genotype in panic disorder patients is associated with increased caffeine-induced anxiety.

This study will study subjects with panic disorder and healthy controls. Based on previous studies the following hypotheses will be tested (2 replication and 2 new hypotheses): Replication; (1) panic disorder subjects will report higher anxiety after a caffeine challenge than the healthy control subjects. (2) healthy controls with the1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to healthy controls with the 1976 C/T and 1976 C/C genotypes, New hypotheses; (3) panic patients (two separate groups: currently ill and remitted) with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to panic patients with the 1976 C/T and 1976 C/C genotypes, (4) panic patients (two separate groups: currently ill and remitted) with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to healthy controls with the 1976 T/T polymorphism will report increased anxiety after a caffeine challenge compared to healthy controls with the 1976 T/T genotype.

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Study Type : Observational
Actual Enrollment : 117 participants
Official Title: Association Between Adenosine Receptor Gene Polymorphisms and Physiological Responses to Caffeine in Subjects With Panic Disorder and Healthy Controls
Study Start Date : May 13, 2004
Study Completion Date : February 14, 2018

Resource links provided by the National Library of Medicine

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

    1. Male or female subjects between ages 18 to 60.
    2. Panic patients with a primary diagnosis of current Panic Disorder without Agoraphobia (300.01) or Panic Disorder with Agoraphobia (300.21) according to DSM-IV criteria. Patients with co-morbid Major Depressive Disorder will be included provided there has been a period of at least 3 months where Panic Disorder, was present in the absence of Major Depressive Disorder or Patients with a past history of Panic Disorder, currently in remission. Remission is defined by as not meeting criteria for Panic Disorder for at least 3 months (no panic attacks in 3 months and less than 5 PDSS score for past month) and off treatment for at least 3 months immediately prior to study entry.
    3. Subjects must be competent to comprehend the purpose of the study and provide written informed consent.
    4. If female, subjects must be: postmenopausal, surgically incapable of childbearing, or practicing medically acceptable method(s) of contraception (eg, hormonal intrauterine device), for at least one month prior to study entry and throughout the study.
    5. Subjects must be psychotropic medication free for at lest 14 days prior to the caffeine/placebo challenge sessions; for fluoxetine at least 4 weeks.
    6. Caffeine free diet for at least 7 days prior to the caffeine/placebo challenge sessions.


  1. Subjects should have no general medical illness that is causing the panic disorder.
  2. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease.
  3. Subjects with known cardiac disease.
  4. Subjects with one or more past seizures without a clear and resolved etiology.
  5. Patients who would be unable to comply with study procedures or assessments.
  6. Patients who are currently at high risk for homicide or suicide.
  7. Patients with psychotic features.
  8. Patients with current DSM-IV substance abuse or dependence within the past year.
  9. Patients who are on a non-psychotropic medication with psychotropic effects (e.g., beta-adrenergic blockers) unless the dosage has been stable for a minimum of one month prior to the study.
  10. Subjects with a positive HIV test result.
  11. Experimental treatment in the past one month.
  12. For healthy volunteers, no current or past history of any psychiatric disorder.
  13. Exclude subjects taking CYP1A2 inhibitors.
  14. Exclude subjects with prostatitis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00083265

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
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Principal Investigator: Daniel S Pine, M.D. National Institute of Mental Health (NIMH)

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Responsible Party: National Institute of Mental Health (NIMH) Identifier: NCT00083265     History of Changes
Other Study ID Numbers: 040183
First Posted: May 17, 2004    Key Record Dates
Last Update Posted: February 16, 2018
Last Verified: February 14, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) ):
Adenosine Receptor
Panic Disorder
Challenge Study
Healthy Volunteer

Additional relevant MeSH terms:
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Panic Disorder
Pathologic Processes
Anxiety Disorders
Mental Disorders
Central Nervous System Stimulants
Physiological Effects of Drugs
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Sensory System Agents
Peripheral Nervous System Agents
Anti-Arrhythmia Agents
Vasodilator Agents
Purinergic P1 Receptor Agonists
Purinergic Agonists