DEPRESSION AND ANXIETY 25:847–853 (2008) Research Article A CAFFEINE CHALLENGE TEST IN PANIC DISORDER PATIENTS, THEIR HEALTHY FIRST-DEGREE RELATIVES AND HEALTHY CONTROLS Antonio E. Nardi, M.D., 1Ã Alexandre M. Valenc - a, M.D., 1 Isabella Nascimento, M.D., 1 Rafael C. Freire, M.D., 1 Andre ´ B. Veras, M.D., 1 Valfrido L. de-Melo-Neto, M.D., 1 Fabiana L. Lopes, M.D., 1 Anna Lucia King, R.A., 1 Gasta ˜o L. Soares-Filho, M.D., 1 Marco A. Mezzasalma, M.D., 1 Arabella Rassi, M.D., 1 and Walter A. Zin, M.D. 2 Our aim was to observe the induction of anxiety symptoms and panic attacks by a caffeine challenge test in panic disorder (PD) patients (DSM-IV) and their healthy first-degree relatives. We randomly selected 25 PD patients, 27 healthy first-degree relatives of probands with PD, and 22 healthy volunteers with no family history of PD. In a randomized double-blind experiment performed over two occasions 7 days apart, 480 mg caffeine and a caffeine-free solution were administered in a coffee form. Using specific panic attack criteria, 52.0% (n 5 13) PD patients, 40.7% (n 5 11) first-degree relatives (v 2 5 1.81, df 5 1, P 5 0.179), and none of the control subjects had a panic attack after the test (v 2 5 51.7, df 5 2, Po0.001). In this caffeine challenge test, PD patients and their first-degree relatives were more sensitive than healthy volunteers to the panic attack symptoms but less sensitive to headache, increase in blood pressure, and insomnia. Our data suggest that there is an association between panic attacks after the intake of 480 mg of caffeine in PD patients and their first-degree relatives. There is a clear differentiation of PD patients and their first-degree relatives by a caffeine test from the healthy group. Depression and Anxiety 25:847–853, 2008. r r 2007 Wiley-Liss, Inc. Key words: panic attacks; coffee; anxiety disorder; comorbidity; stimulant drug INTRODUCTION A high prevalence of anxiety disorders and some biological sensitivity have been found among first- degree relatives of subjects with panic attacks [Perna et al., 1995]. Caffeine is a xanthine derivative that is used worldwide as a psychostimulant and it may be a useful biological model of induced panic attack [Lee et al., 1988; Uhde, 1990, 1995]. There are well- recognized anxiogenic potentials of caffeine, and clinical researchers have been trying to establish its capacity for discriminating panic disorder (PD) patients [Uhde, 1995]. The highly complex mechanisms of caffeine action have been the subject of investigation. The precise mechanism underlying the caffeine panicogenic poten- tials remains unknown, although the most likely mechanism of caffeine’s stimulant effects is considered to be the antagonism of central adenosine receptors [Boulenger et al., 1984; Charney et al., 1985]. It appears to act via multifaceted mechanisms including mobilization of intracellular calcium, phosphodiester- ase inhibition (leading to an increase in intracellular Published online 6 September 2007 in Wiley InterScience (www. interscience.wiley.com). DOI 10.1002/da.20354 Received for publication 18 October 2006; Revised 8 May 2007; Accepted 23 May 2007 Contract grant sponsor: Brazilian Council for Scientific and Technological Development (CNPq); Contract grant number: 554411/2005-9. Ã Correspondence to: Antonio E. Nardi, M.D., Laboratory of Panic & Respiration, Institute of Psychiatry, Federal University of Rio de Janeiro, R. Visconde de Piraja ´, 407/702, Rio de Janeiro-RJ- 22410–003 Brazil. E-mail: antonionardi@terra.com.br 1 Laboratory of Panic & Respiration, Institute of Psychiatry, Rio de Janeiro, Brazil 2 Laboratory of Respiration Physiology, Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil r r 2007 Wiley-Liss, Inc.