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Objective: Previous studies have suggested that manipulations in patient instructions before inhalation of carbon dioxide (C[O.sub.2]) may blunt its anxiogenic effects. The authors examined the effects of a range of instructional types on panic rates and physiological responses to C[O.sub.2] inhalation. Method: Thirty-seven patients with panic disorder and 16 normal subjects were exposed to C[O.sub.2] inhalation under one of three instructional conditions: 1) reassurance (reiterated safety assurances), 2) control dial (patients were instructed on using an operative dial to reduce the concentration of C[O.sub.2] in the breathing canopy), and 3) basic instructions (standard information). Perceived breathlessness was measured with the Borg Scale of Respiratory Exertion. Results: Manipulation of instructional sets did not affect panic rates among patients. The reassurance condition, however, produced a significant reduction in perceived breathlessness. Conclusions: C[O.sub.2]-induced panic is a robust biological effect that occurs independent of cognitive set changes, such as illusion of control or reassurance of safety. Conclusions drawn from this study are bolstered by the fact that it is methodologically rigorous: it had a large number of subjects, used random assignment to one of three instructions, included a full array of both subjective and biological measures, and included independent ratings.

Objective: Whereas the fact of attrition during the course of treatment is well documented, little is known about the factors that affect sample selection before the beginning of a study ('pretreatment attrition'). The present study reports on the degree and sources of pretreatment attrition at two sites of a multicenter study on panic disorder that compared treatment outcomes for imipramine and cognitive behavior therapy. Method: Data were collected at two clinical research sites, one with a pharmacological treatment orientation (N = 420) and one with a psychosocial treatment orientation (N = 208). Results: The main source of pretreatment attrition was participant refusal. At both research sites, eligible patients most often refused participation because they were either unwilling to start treatment with imipramine (30.6% and 47.4%, respectively) or discontinue their current medication (22.6% and 35.1%, respectively). Conclusions: Results from comparative treatment outcome studies are limited not only to people who meet the study criteria but also to those who are willing to begin a medication treatment and discontinue their current medication.

Objective: Respiratory abnormalities may play a central role in the pathophysiology of panic disorder. The current study was undertaken to examine the respiratory response in the largest series of subjects to date during three respiratory challenges that used improved methodology. Method: Fifty-nine patients with DSM-III-R panic disorder and 39 normal volunteers were challenged with 5% and 7% C[O.sub.2] inhalation and room air hyperventilation separated by room air breathing with continuous spirometry. Results: Patients with panic disorder were more sensitive to the anxiogenic effects of C[O.sub.2] than were normal subjects, and C[O.sub.2] was a more potent stimulus to panic than hyperventilation. Patients increased their respiratory rate more quickly during C[O.sub.2] inhalation than did comparison subjects, and this increase preceded the panic attacks. Patients who panicked in response to 5% C[O.sub.2] demonstrated continued rise in end-tidal C[O.sub.2], while the end-tidal C[0.sub.2] of the comparison groups stabilized. Low end-tidal C[O.sub.2] and high variance in minute ventilation at baseline predicted panic attacks during C[O.sub.2] inhalation. Following C[O.sup.2] or hyperventilation challenges, respiratory rate dropped sharply, while tidal volume remained elevated longer in patients than in comparison subjects. Conclusions: The findings confirm the greater behavioral and physiological sensitivity of patients with panic disorder to C[O.sub.2] inhalation and identify a series of respiratory abnormalities. Panic attacks in panic disorder may be explained by inefficient compensatory mechanisms, primarily of respiratory rate.

Objective: To address the lack of a simple and standardized instrument to assess overall panic disorder severity, the authors developed a scale for the measurement of panic disorder severity. Method: Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder (with no or mild agoraphobia) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder. In addition, 89 of these patients were reevaluated with the same scale after short-term treatment. A subset of 24 patients underwent two independent assessments to establish interrater reliability. Internal consistency, convergent and discriminant validity, and sensitivity to change were also determined. Results: The Panic Disorder Severity Scale was associated with excellent interrater reliability, moderate internal consistency, and favorable levels of validity and sensitivity to change. Individual items showed good convergent and discriminant validity. Analysis suggested a two-factor model fit the data best. Conclusions: The Panic Disorder Severity Scale is a simple, efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder. However, further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed.

Objective: Previous studies have indicated that patients with panic disorder are more likely than normal subjects to have acute panic attacks during inhalation of CO2, but methodological objections have been raised. In this study the authors attempted to address three of these methodological problems by ensuring that raters who assessed whether panic attacks occurred were blind to subjects' diagnoses, by randomizing the order of administration of 5% CO2 and hyperventilation, and by challenging a greater number of subjects with 7% CO2. Method: Patients with panic disorder and normal subjects underwent 20-minute inhalations of 5% CO2 and 7% CO2 and 15 minutes of room-air hyperventilation. Ratings of panic/no panic during each condition were made separately by an assessor blind to diagnosis and by the subject. Scores on four panic rating scales were also recorded before and after each intervention. Results: Room-air hyperventilation caused panic attacks in a small number of patients; the difference in panic rate between patients and comparison subjects was statistically significant by the subjects' but not by the raters' assessment. Panic rates during 5% CO2 and 7% CO2 were significantly greater among the patients by both assessments; the panic rate was greatest during 7% CO2. Order of administration did not significantly affect panic rates for hyperventilation and 5% CO2. Conclusions: Panic patients were clearly more sensitive to the anxiogenic effects of CO2 than comparison subjects, and CO2 was a more potent anxiogenic stimulus than room-air hyperventilation. Seven percent CO2 discriminated best between patients and comparison subjects and should be the focus of further research.

Objective: Patients with panic disorder are behaviorally hypersensitive to CO2 inhalation and may also be biologically hypersensitive. A report by Mathew et al. showed, however, that administration of the carbonic anhydrase inhibitor acetazolamide, which is believed to increase brain CO2 level, did not cause panic in panic disorder patients. The authors of the present study noted that respiratory frequency did not increase in the earlier experiment and wondered whether respiratory stimulation occurred during acetazolamide administration, as would be expected if CO2 level increases significantly. Method: Ten patients with panic disorder and six normal control subjects received injections of acetazolamide, 1 g i.v., as per the Mathew et al. protocol, during breath by breath measurement of both tidal volume and frequency of respiration. Results: Three patients had panic attacks, one before receiving acetazolamide, one during the injection, and one 2 minutes after injection. Only the last of these attacks appeared possibly attributable to acetazolamide. None of the control subjects panicked. Neither patients nor control subjects exhibited meaningful change in tidal volume, respiratory frequency, or minute ventilation, and both groups experienced a trend toward significant decrease in overall levels of anxiety and dyspnea after acetazolamide injection. Conclusions: The authors replicated the earlier finding that acetazolamide is not panicogenic in patients with panic disorder but also showed that at the dose given, there is no meaningful effect on ventilation. If acetazolamide does affect CO2 levels it does so in a way that does not stimulate ventilation. Therefore, the acetazolamide injection results of Mathew et al. and of the present study do not challenge hypotheses linking panic attacks to hypersensitive respiratory control mechanisms.

Objective: The purpose of this article is to offer a comprehensive, data-based explanation of the relationship between hyperventilation and panic disorder linking CO2 hypersensitivity, cognitive/behavioral factors, and the respiratory effects of antipanic pharmacologic and psychological treatments. Method: The authors conducted a computerized search of MEDLINE for relevant articles. Results: Some panic patients have a chronic, subtle respiratory disturbance. Acute hyperventilation is neither necessary nor sufficient for panic to occur. Respiratory abnormalities in panic patients may adaptively aim at coping with a hypersensitive CO2 chemoreceptor system. Pharmacologic panicogens also stimulate the respiratory system, causing hyperventilation. Triggering this hypersensitive respiratory control mechanism may incite panic. Antipanic medications may reset the receptor threshold. Misattribution and catastrophic interpretation of somatic symptoms or the sense of loss of control may contribute to panic symptoms. Behavioral interventions such as desensitization or breathing retraining may block the full-blown attack. Cognitive strategies through cognitive control of respiration may supplement and accentuate these interventions. Conclusions: Panic disorder may be due to an inherently unstable autonomic nervous system, coupled with cognitive distress.

Objective: The authors assessed the substance and diagnostic specificity of carbon-dioxide-induced panic since, in addition to the specific biochemical effects of inhaled carbon dioxide (CO2), simple physiologic distress is also frequently implicated as a panicogenic factor during respiratory challenge studies with CO2 in patients with anxiety disorders. Method: Eighteen patients with panic disorder, 20 with social phobia, and 23 psychiatrically normal subjects inhaled a mixture of 35% CO2 and 65% O2 for 30 seconds through a face mask. They also breathed for 30 seconds through a valve reducing the diameter of the airway. A double-blind, counterbalanced, randomized design was used. Results: In spite of important similarities between the two interventions, including the induction of equal amounts of subjective respiratory distress, carbon dioxide inhalation was significantly more potent than increased airway resistance in provoking panic in the anxiety disorder patients. The patients with panic disorder were significantly more sensitive to CO2 than were the patients with social phobia or the normal subjects. Conclusions: Carbon dioxide inhalation appears to have a specific panicogenic effect in panic patients that goes beyond simple breathlessness. (Am J Psychiatry 1993; 150:250-257)

There is considerable evidence that cognitive-behavioral psychotherapy can provide a useful alternative to drugs for treating panic disorder and related syndromes. However, most studies that have demonstrated the benefit of cognitive-behavioral therapy have been conducted by cognitive-behavioral therapists. Therefore, it is difficult to rule out potential bias within the study results favoring this approach. A study was designed in which 24 patients with panic attacks were treated by therapists who were not experienced in cognitive-behavioral therapy. The therapists included the staff of a psychiatric center that was oriented towards the use of psychoactive drugs. The staff members were briefly trained by a behavioral therapist on the application of cognitive-behavioral methods to panic disorder. Nineteen of the 24 patients completed the program. Fourteen reported being free of panic at the end of the treatment, and three more patients reported a significant reduction in the frequency and severity of panic attacks. These results indicate that it is likely to be the method of cognitive-behavioral therapy, rather than the orientation of the therapist, that is the most important factor in determining successful treatment of panic disorder. The authors provide a discussion of methods for training mental health personnel in cognitive-behavioral methods and a discussion of the problems of introducing these methods to psychiatric centers that emphasize drug therapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: The behavioral response to [CO.sub.2] inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of [CO.sub.2]-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to [CO.sub.2] inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). Method: The behavioral responses to inhalation of 5% and 7% [CO.sub.2], administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each [CO.sub.2] inhalation. Results: Panic disorder patients had a higher rate of [CO.sub.2]-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with [CO.sub.2]-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent [CO.sub.2] was a more robust panicogen than 5%, and response to 7% [CO.sub.2] better distinguished panic disorder patients from normal subjects than response to 5% [CO.sub.2]. Conclusions: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to [CO.sub.2]-induced panic attacks, and depressed patients appear to be insensitive to [CO.sub.2] inhalation. The symptoms of [CO.sub.2]-induced panic attacks have a similar intensity regardless of the subject's diagnosis. (Am J Psychiatry 2001; 158:58-67)

Twenty panic disorder patients with mitral valve prolapse showed amelioration of prolapse on repeat echocardiogram after treatment for panic disorder. This effect was significant when compared to repeat echocardiograms in eight psychiatrically normal control subjects with mitral valve prolapse. (Am J Psychiatry 1992; 149:1587-1588)

Studies have shown that inhalation of carbon dioxide can induce panic in panic disorder patients, the point of panic coinciding with high carbon dioxide concentrations in the blood. Panic patients may be hypersensitive to carbon dioxide. Patients with a history of panic attacks and control subjects were placed under a clear plastic canopy and told that carbon dioxide would be added to the air they were breathing and that they might experience anxiety. The patients were given room air for 20 minutes; five percent carbon dioxide was added to the room air for another 20 minutes without their knowledge. Blood samples were monitored for carbon dioxide concentrations, and the patients were told to report any symptoms as soon as they occurred. The male panic patients were significantly more sensitive to carbon dioxide than the male control subjects, but anxiety levels in both groups were low and did not differ significantly. The data also suggested that there may be sex differences in panic disorder and that female panic patients may not be hypersensitive to carbon dioxide. Psychological factors known to affect carbon dioxide sensitivity were not controlled, but all subjects received the same instructions and experienced the same degree of anxiety. The physiologic differences that were recorded did not seem to be related to the levels of anxiety experienced by the subjects. (Consumer Summary produced by Reliance Medical Information, Inc.)