232 Martinez et al. © 2001 WILEY-LISS, INC. DEPRESSION AND ANXIETY 14:232–237 (2001) RESPIRATORY VARIABILITY IN PANIC DISORDER J.M. Martinez, M.A.,* J.M. Kent, M.D., J.D. Coplan, M.D., S.T. Browne, B.A., L.A. Papp, M.D., G.M. Sullivan, M.D., M. Kleber, Ph.D., F. Perepletchikova, B.A., A.J. Fyer, M.D., D.F. Klein, M.D., and J.M. Gorman, M.D. Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO 2 inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the nor- mal control group. Panic disorder patients who panicked to 7% CO 2 inhala- tion had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO 2 -induced panic. Depression and Anxiety 14:232–237, 2001. © 2001 Wiley-Liss, Inc. Key words: respiration; variability; panic disorder; fear; trait Department of Psychiatry, Columbia University, and Depart- ments of Clinical Psychobiology and Therapeutics, New York State Psychiatric Institute, New York, New York. Contract grant sponsor: MHCRC; Contract grant numbers: MH- 30960, MH-41778; Contract grant sponsor: Senior Scientist Award; Contract grant number: NIH-00416; Contract grant sponsor: Inde- pendent Scientist Award; Contract grant number: MH-01397; Con- tract grant sponsor: Center for Neuroscience; Contract grant number: MH-58911-P50. *Correspondence to: Jose Martinez, Department of Psychiatry, Columbia University, 1051 Riverside Drive, Unit 14, New York, NY 10032. E-mail: josemar@pi.cpmc.columbia.edu Received for publication 6 June 2000; Revised 1 June 2001; Ac- cepted 4 October 2000 INTRODUCTION P anic disorder (PD) has been linked to respiratory abnor- malities ranging from benign chronic hyperventilation with associated hypocapnia to hypersensitive respiratory control systems [Sinha et al., 2000; Wilhelm et al., 2001a]. Our group has previously found, in two separate stud- ies, that panic disorder subjects have greater respiratory variability than comparison subjects. One study [Papp et al., 1997] found that female panic disorder subjects had greater within-subject standard deviations for tidal vol- ume and minute ventilation compared to female controls at baseline in the laboratory. Another study [Martinez et al., 1995], which recorded ambulatory respiration of panic disorder subjects outside of the laboratory, found greater variability in minute ventilation during sleep and greater variability of tidal volume during symptomatic periods while awake. Other investigators have shown ir- regularity in breathing patterns in panic disorder subjects at rest (particularly greater variability in tidal volume) [Wilhelm et al., 2000a; Abelson et al., 1996, 2001] and during sleep [Stein et al., 1995]. Recent studies also dem- onstrated greater tidal volume instability in PD subjects than in patients with generalized anxiety disorder (GAD) [Wilhelm et al., 2001a] and a greater frequency of sigh- ing in PD subjects [Wilhelm et al., 2001a,b; Abelson et al., 2001]. In total, these reports suggest an intrinsic ir- regularity in breathing, which may be due to instability in the autonomic control of respiration in panic disorder.