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.
* 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 sessions. EXCLUSION CRITERIA: 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.