Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder

OBJECTIVE: The behavioral response to CO(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(2)-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO(2) inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO(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(2) inhalation. RESULTS: Panic disorder patients had a higher rate of CO(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(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(2) was a more robust panicogen than 5%, and response to 7% CO(2 )better distinguished panic disorder patients from normal subjects than response to 5% CO(2). CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO(2)-induced panic attacks, and depressed patients appear to be insensitive to CO(2) inhalation. The symptoms of CO(2)-induced panic attacks have a similar intensity regardless of the subject's diagnosis.     

Panic induced by carbon dioxide inhalation and lack of hypothalamic-pituitary-adrenal axis activation.

It has been hypothesized that spontaneous panic is distinct from anticipatory anxiety, which activates the hypothalamic-pituitary-adrenal (HPA) axis. Panic attacks characterized by prominent respiratory symptoms, such as those induced by sodium lactate, are not associated with increases in cortisol. We examined blood cortisol responses to CO2-induced panic. Cortisol levels did not increase and actually decreased significantly in 10 panicking subjects with panic disorder. No reductions were noted after 20 min of CO2 inhalation in either eight normal comparison subjects or six non-panicking panic disorder patients. These results lend support to the hypothesis that the pathophysiological mechanism underlying CO2-induced panic is different from that underlying general or anticipatory anxiety.     

Noradrenergic function and the mechanism of action of antianxiety treatment. II. The effect of long-term imipramine treatment

Considerable preclinical and clinical evidence indicates that increased noradrenergic function is involved in the development of anxiety. Imipramine hydrochloride, which has complex effects on noradrenergic function in animals, is effective in patients with agoraphobia and panic disorder. To assess the effects of imipramine on noradrenergic function in patients, plasma levels of free 3-methoxy-4-hydroxyphenylglycol (MHPG) and yohimbine-induced increases in plasma MHPG levels, anxiety-nervousness, blood pressure, and somatic symptoms were studied before and during long-term imipramine treatment in 11 patients meeting DSM-III criteria for agoraphobia with panic attacks. Long-term imipramine treatment significantly decreased baseline plasma MHPG levels by 38% and modestly potentiated yohimbine-induced increases in blood pressure, but it did not alter yohimbine-induced increases in plasma MHPG levels or in patient ratings of anxiety-nervousness. The therapeutic effects of imipramine in panic disorder may relate more to the decrease in norepinephrine turnover than to alterations of alpha 2-adrenergic autoreceptor function.     

Stress responsivity and HPA axis activity in juveniles: results from a home-based CO2 inhalation study

OBJECTIVE: A previous laboratory-based study found elevated cortisol levels in anxious children susceptible to CO(2)-induced panic, but the effects of parent diagnosis were not considered. The current home-based study tested the hypothesis that parental panic disorder and offspring response to CO(2) are associated with elevated cortisol levels in juvenile offspring. METHOD: A total of 131 offspring (ages 9-19) of parents with panic disorder, major depression, and no mental disorder underwent CO(2) inhalation. Parent and child diagnoses were assessed. Salivary cortisol was assayed before and after CO(2) inhalation. RESULTS: Neither parents with panic disorder, parents with major depression, or offspring anxiety predicted offspring cortisol levels. Independent of parent and child diagnoses, anxiety response to CO(2) predicted elevated cortisol levels in offspring. CONCLUSIONS: As in adults, anxiety response to CO(2) in juveniles is associated with elevated cortisol levels, but elevated cortisol levels are not related to parent or child diagnoses.     

Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone

Data from 74 patients with panic disorder were evaluated to determine the comparative efficacy of imipramine, alprazolam, and trazodone. All patients were treated with placebo for 3 weeks and were then blindly switched to active treatment for 8 weeks. Both imipramine and alprazolam were highly effective in reducing the symptoms of generalized anxiety, the frequency of panic attacks, and phobic avoidance. However, the time course of these effects differed; alprazolam demonstrated therapeutic properties during the first week, whereas the therapeutic efficacy of imipramine was not clearly apparent until the fourth week of treatment. Relative to imipramine and alprazolam, trazodone was not an effective treatment for panic disorder and was poorly tolerated; only 17 trazodone-treated patients completed at least 4 weeks of treatment, and only 2 patients were considered good or complete responders. These findings support the hypotheses that drugs that are efficacious in the treatment of panic disorders act by altering noradrenergic function and that drugs with primary actions on serotonin function are likely to be less effective treatments. The different time courses of therapeutic action of imipramine and alprazolam indicate that these drugs ameliorate panic anxiety via different mechanisms. The possible therapeutic applications of this observation are discussed.     

Sequential combination of imipramine and self-directed exposure in the treatment of panic disorder with agoraphobia

Thirty-eight patients who had panic disorder with agoraphobia completed 8 weeks of treatment with imipramine followed by 8 weeks of treatment with imipramine combined with behavior therapy consisting of self-directed exposure. Sixty-three percent (24) of the patients responded markedly to this cost-effective combined pharmacologic and behavioral approach. Results also revealed that most of the improvement in panic occurred during the first 8 weeks of treatment when imipramine treatment alone was used, whereas improvement in severity, anxiety, depression, and phobias, in particular, continued to be significant between midtreatment and end of study. Further analysis revealed that improvement in phobic anxiety and avoidance in the first 8 weeks of treatment, rather than improvement in panic, predicted final outcome. Implications of these findings on the complex issue of differential antipanic and antiphobic effects of imipramine are briefly discussed.     

Reduction of CO2-induced anxiety in patients with panic attacks after repeated CO2 exposure

The authors compared the subjective reaction of 13 panic patients and eight control subjects to a 35% CO2 challenge, a treatment known to produce physical symptoms comparable to those of natural or lactate-induced panic, and to placebo treatment (inhalation of air). They found that patients had higher placebo scores than control subjects, patients tended to get highly anxious on CO2 and control subjects did not, and CO2-induced subjective anxiety in patients decreased as the number of CO2-induced exposures to interoceptive anxiety symptoms increased. The data support a behavioral account of the effects of anxiogenics.     

Vulnerability to 35% CO2 of panic disorder patients with a history of respiratory disorders

Patients with panic disorder often report a history of respiratory pathology. Furthermore, panic disorder patients are vulnerable to CO2 challenges. The increased CO2 vulnerability displayed by panic disorder patients may be related to lifetime respiratory pathology. We examined whether panic disorder patients with a history of respiratory disorders are more vulnerable to a 35% CO2 challenge than those without such a history. Ninety-six patients with panic disorder were interviewed about their lifetime respiratory status (asthma, bronchitis and various other respiratory conditions) and underwent the challenge. Immediately before and after the CO2 inhalation, the patients filled out the Visual Analogue Scale for Anxiety (VAS-A) and the Panic Symptom List (PSL). We found no differences between the two panic disorder groups on anxiety (VAS-A), panic symptoms (PSL) or panic attacks after the CO2 challenge. Our results suggest that having a PD is an important factor in CO2 vulnerability independent of a history of respiratory disorders.     

Respiratory variability in panic disorder.

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 normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation 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.     

Anxiety sensitivity does not predict fearful responding to 35% carbon dioxide in patients with panic disorder

The aim of the present study was to examine the relationship between anxiety sensitivity, as measured by the Anxiety Sensitivity Index (ASI), and four dimensions of behavioural reactivity to a single inhalation of 35% carbon dioxide (CO(2)) in 31 patients with panic disorder. ASI scores correlated positively with baseline State-Trait Anxiety Inventory scores but did not correlate with post-CO(2) scores. Correlational analyses revealed a significant, albeit modest, correlation between anxiety sensitivity and cognitive symptoms induced with CO(2). However, no significant association was found between anxiety sensitivity and other dimensions of CO(2)-induced anxiety, including severity of somatic symptoms, subjective levels of anxiety, fear or apprehension, and fear of the somatic symptoms induced by CO(2). Overall, these data do not support the view that anxiety sensitivity plays a key role in mediating behavioural sensitivity to CO(2) inhalation in panic disorder.     

Avoidance behaviour: A predictor of the efficacy of pharmacotherapy in panic disorder?

Summary The impact of the avoidance behaviour on the psychopharmacological treatment of panic disorder was explored in the Cross National Collaborative Panic Study (n=1134 patients); in this double blind randomized trial alprazolam, imipramine and placebo were compared during an 8-week treatment period. Patients with extensive avoidance behaviour (agoraphobia) had the most profit from the active drugs. Counter expectancy these specific drug effects were most pronounced in avoidance behaviour. Active drugs (in particular imipramine) were especially more effective than placebo if the patients presented with associated avoidance behaviour. The results suggest that agoraphobia defines more a particular type of anxiety disorder overlapping with panic disorder than merely a severe state of panic disorder.     

Effects of the cortisol synthesis inhibitor metyrapone on the response to carbon dioxide challenge in panic disorder

Despite the well-known association between the hypothalamic-pituitary-adrenal (HPA) axis and normal fear, it is still unclear (a) to what extent corticotropin releasing hormone (CRH) or cortisol itself mediates fear responses, and (b) to what extent the HPA axis also affects panic disorder. The carbon-dioxide (CO2) challenge has been proposed as a model for panic. Participants received the cortisol synthesis inhibitor metyrapone 30 mg/kg of body weight once and placebo once, with 1 week between challenges, at 2300 h. The following morning, blood was taken for cortisol and ACTH levels, and then participants inhaled a single vital capacity inhalation of 35% CO2 and 65% oxygen. Before and after the inhalation, participants completed an inventory of the 13 DSM-IV symptoms of panic and the NIMH questionnaire of psychological and physical symptoms. Eight healthy controls and 14 patients with panic disorder completed the protocol. As expected, CO2 increased measures of anxiety, and metyrapone lowered cortisol and increased ACTH levels. Prechallenge anxiety was modestly lowered by metyrapone, but response to CO2 was not affected. Cortisol and ACTH levels before challenge partly predicted the response to CO2. The results support an anxiogenic role for cortisol in stress, and suggest that the pathophysiological mechanism that mediates CO2-induced panic differs from those underlying other kinds of anxiety.     

The acute antipanic and anxiolytic activity of aerobic exercise in patients with panic disorder and healthy control subjects

Regular physical activity is anxiolytic in both healthy subjects and patients with panic disorder. In contrast, acute exercise may induce acute panic attacks or increase subjective anxiety in patients with panic disorder more than in other people. The effects of quiet rest or an aerobic treadmill exercise (30 min at an intensity of 70% of the maximal oxygen uptake, VO_2max) on cholecystokinin tetrapeptide (CCK-4) induced panic attacks were studied in a crossover design in 12 patients with panic disorder and 12 matched healthy subjects. The effects of CCK-4 (25 μg in patients and 50 μg in control subjects) were measured with the Acute Panic Inventory (API) score, comparing panic attack frequencies, total score, and subscores for anxiety and somatic symptoms. CCK-4-induced panic attacks were less frequent after prior exercise: they occurred in 15 (62.5%) subjects after rest (9 patients and 6 control subjects), but only 5 (20.8%) subjects after exercise (4 patients and 1 control subject). In both conditions, CCK-4 administration induced a significant increase in the total API score and the anxiety and somatic symptoms subsores. However, compared to prior rest, exercise resulted in a significantly reduced CCK-4-induced increase of the total API score and the anxiety subscore. In patients with panic disorder exercise increased the total API score and the somatic symptoms subscale but not the anxiety subscore. Patients with panic disorder showed increased somatic but not anxiety symptoms after an acute bout of exercise. Severity of CCK-4-induced panic and anxiety, on the other hand was reduced by exercise. These findings suggest that in addition to exercise training an acute bout of exercise may be used to reduce anxiety and panic attack frequency and intensity in panic disorder patients.     

Sensitivity to carbon dioxide in drug-naïve subjects with post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is currently classified as an anxiety disorder in DSM-IV, and as a neurosis or stress-related disorder in ICD-10. It shares many features with depression. Sensitivity to carbon dioxide (CO2), a classic provocation agent in the proto-typical anxiety disorder, panic disorder, has not been tested in PTSD. Twenty rigorously ascertained drug-na?ve subjects with PTSD inhaled a single vital capacity inhalation of 35% CO2; before and after the inhalation they completed measures of PTSD and panic anxiety, and were rated for the presence of a panic attack. These results were retrospectively compared with those of 39 healthy volunteers and 17 patients with panic disorder previously studied by the same research group. PTSD symptoms were not exacerbated by CO2. Two out of twenty PTSD subjects panicked. PTSD subjects' responses were indistinguishable from those of healthy volunteers, and differed from those of subjects with panic disorder. The lack of sensitivity to carbon dioxide in PTSD subjects in the present study adds to the literature on the differences between PTSD and other anxiety disorders, and to that on the specificity of the CO2 challenge in panic disorder.     

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder

OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.     

Anxiety sensitivity and CO2 challenge reactivity as unique and interactive prospective predictors of anxiety pathology

Emerging evidence suggests that anxiety sensitivity (AS) and CO(2)-induced fear reactivity are associated with panic attacks and anxiety disorders. However, evidence regarding the unique and potentially synergistic effects of these variables is currently lacking. Our primary aims in this study were to determine whether AS and CO(2)-induced fear reactivity are unique and potentially interactive vulnerability factors involved in the pathogenesis of panic attacks and anxiety psychopathology. A large nonclinical sample of young adults (N=404) was prospectively followed over approximately 2 years. AS (i.e., 16-item Anxiety Sensitivity Index total scores) and biological challenge reactivity [i.e., fearful responding to pre- and postchallenge changes in subjective units of distress (SUDS) to a 20-s 20% CO(2) challenge] at study entry served as the primary predictor variables. Consistent with expectation, AS and challenge reactivity correlated only moderately with one another. Challenge reactivity was uniquely associated with the development of spontaneous panic attacks, whereas AS was uniquely associated with anxiety disorder diagnoses, including panic disorder. Moreover, the combination of both risk factors predicted spontaneous panic attacks beyond the effects of either risk factor individually. These data provide novel evidence for the unique and combined effects of AS and CO(2)-induced fear reactivity as risk factors in the development of anxiety and its disorders.     

Response to 35% CO2 as a marker of panic in severe anxiety

One inhalation of 35% CO2 was administered to each of 32 patients with high anxiety ratings. Only patients with panic disorder had increases in reported anxiety upon CO2 intake. CO2-triggered anxiety appears specific for panic disorder and independent of baseline anxiety.     

Sensitivity to 35% carbon dioxide in patients with generalized anxiety disorder.

BACKGROUND: Panic disorder and generalized anxiety disorder (GAD) are both characterized by severe anxiety, but there is evidence that indicates a qualitative difference between these 2 anxiety disorders. To investigate the specificity of the association between carbon dioxide (CO2) hypersensitivity and panic disorder and the possible relationships between panic disorder and GAD, the responses to inhalation of a gas mixture of 35% CO2 and 65% oxygen (O2) were assessed. METHOD: Fifteen patients with panic disorder, 13 patients with GAD, and 10 patients with comorbid GAD and panic disorder according to a consensus diagnosis using Diagnostic Interview Schedule Version III-R (DIS-R) and DSM-IV criteria, and 12 healthy controls inhaled 2 vital capacities: 1 of 35% CO2 and 1 of compressed air. A double-blind, randomized, crossover design was used. RESULTS: GAD patients showed reactions to 35% CO2 that were similar to those of healthy controls and significantly weaker than that of panic disorder patients. Patients with comorbid panic disorder and GAD had anxiogenic reactions similar to those of subjects with panic disorder. CONCLUSION: The results of the present study support the idea that panic disorder and GAD are separate disorders that have at least some differences in pathogenetic mechanisms and suggest that the 35% CO2 test might be a valid tool for discriminating between these 2 disorders.     

Specific sensitivity of patients with panic attacks to carbon dioxide inhalation

One inhalation of 35% CO2 in oxygen was administered to 36 patients with anxiety disorders and 14 healthy controls. Eighteen patients had a diagnosis of panic disorder (PD) and 18 of obsessive-compulsive disorder (OCD). As a placebo control for CO2, compressed air was administered in a double-blind design. Immediately before and after the inhalation, levels of anxiety and DSM-III-R symptoms of panic were assessed. CO2 elicited high levels of subjective anxiety in the PD group. Patients with OCD were hardly affected by the inhalation, and did not differ from healthy controls. These results suggest that CO2 challenge should be considered as a specific probe for subjects with panic-anxiety. It is speculated that CO2 may trigger some as yet undefined mechanisms, possibly linked to ventilation control, which demarcate panic from other types of pathological anxiety.     

Imipramine and alprazolam effects on stress test reactivity in panic disorder.

The reactivity of 40 panic disorder patients on mental arithmetic, cold pressor, and 5% CO2 inhalation stressors was tested before and after 8 weeks of treatment with imipramine, alprazolam, or placebo. Mean levels of subjective and physiological stress measures were compared during a baseline before any stressors were given, and at anticipation, stressor, and recovery periods for each stressor. After treatment, imipramine patients differed from the other two treatment groups on the prestressor baseline in showing higher systolic blood pressure (mean difference about 10 mmHg), higher diastolic blood pressure (10 mm Hg), higher heart rate (15 bpm), less respiratory sinus arrhythmia, shorter pulse transit time, and lower T-wave amplitude. Respiratory measures, electrodermal measures, body movement, and self-reported anxiety and excitement did not distinguish the groups. Reactivity to the stress tests was unaffected by the medications, but tonic differences present in the baseline persisted.