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
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.
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
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.
- INCLUSION CRITERIA:
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
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.