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.     

Differential carbon dioxide sensitivity in childhood anxiety disorders and nonill comparison group

BACKGROUND: To examine the relationship between respiratory regulation and childhood anxiety disorders, this study considered the relationship between anxiety disorders and symptoms during carbon dioxide (CO(2)) exposure, CO(2) sensitivity in specific childhood anxiety disorders, and the relationship between symptomatic and physiological responses to CO(2). METHODS: Following procedures established in adults, 104 children (aged 9-17 years), including 25 from a previous study, underwent 5% CO(2) inhalation. The sample included 57 probands with an anxiety disorder (social phobia, generalized anxiety disorder, separation anxiety disorder, and panic disorder) and 47 nonill comparison subjects. Symptoms of anxiety were assessed before, during, and after CO(2) inhalation. RESULTS: All children tolerated the procedure well, experiencing transient or no increases in anxiety symptoms. Children with an anxiety disorder, particularly separation anxiety disorder, exhibited greater changes in somatic symptoms during inhalation of CO(2)-enriched air, relative to the comparison group. During CO(2) inhalation, symptom ratings were positively correlated with respiratory rate increases, as well as with levels of tidal volume, minute ventilation, end-tidal CO(2), and irregularity in respiratory rate during room-air breathing. CONCLUSIONS: Childhood anxiety disorders, particularly separation anxiety disorder, are associated with CO(2) hypersensitivity, as defined by symptom reports. Carbon dioxide hypersensitivity is associated with physiological changes similar to those found in panic disorder. These and other data suggest that certain childhood anxiety disorders may share pathophysiological features with adult panic disorder.     

Patterns of psychopathology and dysfunction in high-risk children of parents with panic disorder and major depression

OBJECTIVE: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. METHOD: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). RESULTS: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and poorer social functioning in offspring. Both parental panic disorder and parental major depression, individually or comorbidly, were associated with increased risk for separation anxiety disorder and multiple (two or more) anxiety disorders in offspring. CONCLUSIONS: These findings confirm and extend previous results documenting significant associations between the presence of panic disorder and major depression in parents and patterns of psychopathology and dysfunction in their offspring.     

Acute panic inventory symptoms during CO(2) inhalation and room-air hyperventilation among panic disorder patients and normal controls.

There is scant literature on anxiety symptoms induced during respiratory challenges developed to induce panic symptoms and attacks. Here we report on the prevalence of Acute Panic Inventory (API) symptoms during three consecutive respiratory challenges to patients with panic disorder (PD) and normal controls (NC). The challenges performed using a closed canopy system included voluntary room air hyperventilation (RAH), inhalation of 5% CO(2), and 7% CO(2)-enriched air. The PD patients were 41 men and 53 women whose mean age was 33.4 (SD = 8.55). The normal comparison group consisted of 35 men and 27 women with a mean age of 31.3 (SD = 9.21). The diagnosis of panic disorder was made using the Structured Clinical Interview for DSM-III-R. All potential normal controls underwent structured clinical interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version Modified for the Study of Anxiety Disorders (SADS-LA), and must have been free of a lifetime history of anxiety disorders, affective disorders, substance use disorders, and schizophrenia. All participants also had a complete medical evaluation and were in good health. The experiment consisted of seven experimental epochs: three baseline/recovery periods each followed by a respiratory challenge, and then a final recovery epoch. The API was administered at the end of each epoch. Clinical staff trained and experienced in rating panic attacks rated participants' response during each challenge as panic or no panic. Three groups were defined for analysis: PD patients who panicked, PD patients who did not panic, and NC who did not panic. Staff ratings indicated that the 7% CO(2) challenge was the most panicogenic, followed by the 5% CO(2), and the RAH challenges. Conventional statistics (analysis of variance and partial correlations) indicated that many baseline symptoms as well as symptom increments differed across groups, and were associated with the outcome of panic/no panic during each challenge. However, logistic regression analysis indicated that only a few symptoms independently predicted the panic/no panic outcome because many symptoms were redundant. The symptom cluster of fear in general, dizziness, difficulties with concentrating, and doing one's job predicted panic to RAH. The cluster of fear in general, confusion, dyspnea, and twitching/trembling predicted the response to 5% CO(2). Finally, fear in general, confusion, twitching/ trembling and dizziness predicted the response to 7% CO(2). While univariate analyses indicated that many symptoms distinguished between panic and no panic outcome, logistic regression revealed that group differences were subsumed under a few prominent symptoms, namely, fear in general, confusion, dizziness, twitching/trembling, and dyspnea. The results are discussed in the context of patient (having a diagnosis of PD) and panic effects (rated as panicking to a challenge).     

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.     

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.     

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.     

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.     

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.     

Depression and anxiety disorders in parents and children. Results from the Yale family study

The children (aged 6 to 17 years) of probands with primary major depression, with and without various anxiety disorders, were compared with the children of a matched normal control group. The results from the study of these young children parallel our previous findings among the adult first-degree relatives of these probands. Depression in the proband increased the risk of depression in the children. Depression plus panic disorder or agoraphobia in the proband conferred an additional risk of depression and of an anxiety disorder in the children. Panic disorder in the parents conferred more than a threefold increased risk of separation anxiety in the children. Other factors that increased the risk to children were degree of familial loading for psychiatric illness, parental assortative mating, and parental recurrent depression. The findings suggest a relationship between depression and some of the anxiety disorders, and between adult panic disorder and agoraphobia and transmission of anxiety disorders to children.     

Familial aggregation of panic disturbances in Parkinson's disease

Panic disorder has an elevated prevalence in Parkinson's disease (PD). To explore the basis for this co-occurrence, the familial aggregation of panic disorder was examined in patients with PD. Probands and relatives of patients with PD and panic disorder (PD-PANIC; N=20, N=115) and control probands with PD and no active psychiatric illness (PD-NA; N=17, N=108) were interviewed by phone, using a structured interview to determine panic status. Lifetime prevalence of panic and "panic-like" disorders was higher in PD-PANIC than in PD-NA relatives. Panic and "panic-like" disorders are familial disorders in PD.     

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.     

Developmental trajectories of anxiety disorders in offspring at high risk for panic disorder and major depression

The objective of this study was to evaluate the longitudinal course of psychiatric disorders in children of parents with and without panic disorder and major depression as they transition through the period of risk from early to late childhood. Over a 5-year follow-up, we compared the course of psychiatric disorders in offspring of parents with panic disorder, major depression, or neither disorder. Subjects consisted of 233 offspring (from 151 families) with baseline and follow-up assessments. Subjects were comprehensively assessed with structured diagnostic interviews. Anxiety disorders at baseline were used to predict anxiety disorders and major depression at follow-up using stepwise logistic regression. Separation anxiety disorder significantly increased the risk for the subsequent development of specific phobia, agoraphobia, panic disorder, and major depression, even after parental panic and depression were covaried. Agoraphobia significantly increased the risk for subsequent generalized anxiety disorder. These findings suggest that separation anxiety disorder is a major antecedent disorder for the development of panic disorder and a wide range of other psychopathological outcomes, and that it increases the risk for subsequent psychopathology even among children already at high familial risk for anxiety or mood disorder.     

The Panic Disorder Respiratory Ratio: A Dimensional Approach to the Respiratory Subtype

ObjectiveThe respiratory ratio is a dimensional construct of the respiratory subtype of panic disorder (PD). The respiratory subtype has been correlated with an increased sensitivity to CO2 inhalation, positive family history of PD and low comorbidity with depression. The objective of our study was to determine whether the respiratory ratio is correlated with CO2-induced panic attacks and other clinical and demographic features.MethodsWe examined 91 patients with PD and submitted them to a double-breath 35% CO2 challenge test. The respiratory ratio was calculated based on the Diagnostic Symptom Questionnaire (DSQ) scores recorded in a diary in the days preceding the CO2 challenge. The scores of the respiratory symptoms were summed and divided by the total DSQ score.ResultsThe respiratory ratio was correlated with CO2 sensitivity, and there was a non-statistically significant trend towards a correlation with a family history of PD.ConclusionsThe positive correlation between the respiratory ratio and the anxiety elicited by the CO2 inhalation indicates that the intensity of respiratory symptoms may be proportional to the sensitivity to carbon dioxide.     

Relations between anxiety sensitivity and panic symptoms in nonreferred children and adolescents

Anxiety sensitivity (AS), the fear of anxiety-related sensations, has been posited to be a cognitive risk factor for the development of anxiety disorders but has been understudied in youth. The purpose of the present investigations was to evaluate relations between AS and panic symptoms in nonreferred children and adolescents. In Study 1, (N = 113, mean age, 13.98). scores on the Childhood Anxiety Sensitivity Index (CASI) predicted the experience of uncued panic attacks after controlling for general anxiety and depression, although the total variance accounted for was small. In Study 2 (N = 52; mean age, 9.48), the Panic/ Agoraphobia subscale of the Spence Children's Anxiety Scale was used as the criterion variable. CASI score again predicted panic symptoms after controlling for trait anxiety and depression. Identification of a risk factor for panic attacks and panic disorder in youth will have important implications for etiologic theory, intervention, and prevention.     

Response to 35% CO2 in patients with chest pain and angiographically normal coronary arteries.

OBJECTIVES: Several interview studies have suggested that panic disorder (PD) exists in patients with angiographically normal coronary arteries (NCA). Interview studies require corroboration by other studies in order to validate them. The purpose of this study is to test whether response to the inhalation of 35% CO2 reliably discriminates between PD and non-panic disorder patients in this population. METHOD: Three groups were studied: six with NCA and PD, five with NCA and no PD, and ten in the control group. All subjects breathed room air, then 35% CO2 in a single-blind fashion. Each completed the Acute Panic Inventory (API) before and during the procedure. RESULTS: The NCA-panic group scored significantly higher than the other two groups on the Acute Panic Inventory from baseline to post-inhalation. CONCLUSION: Despite several methodological limitations including a relatively small number people in each cells, 35% CO2 was shown to trigger more intense responses in panic patients, thus helping to validate the interview findings.     

High-dose carbon dioxide challenge test in anxiety disorder patients

Many investigators have shown that panic disorder patients and possibly social phobics are hypersensitive to the anxiogenic effects of inhaled carbon dioxide (CO2). In this study we administered double-breath inhalation of 35% CO2 and 65% oxygen (O2) to panic disorder patients, social phobics, and normal controls. At baseline, panic disorder patients were characterized by higher pulse, anxiety score, and evidence of hyperventilation. Panic patients and social phobics panicked more often to 35% CO2 than to room air; normal controls did not have a higher rate of panic to CO2 than to room air. However, we did not find significant group differences in anxiety level, physiological measures, or biochemical measures in response to CO2 breathing compared with room air breathing. These results confirm earlier reports of baseline hyperventilation in panic disorder patients. However, 35% CO2 may be too high a dose to differentiate respiratory responses of patients compared with normals.     

Aberrant respiratory sensitivity to CO(2) as a trait of familial panic disorder.

BACKGROUND: According to three earlier studies, well individuals with a family history of panic disorder experience more anxiety following a single breath of 35% CO(2) than do those without such a family history. This study sought to determine whether a heightened sensitivity to CO(2) manifests specifically in respiratory changes. METHODS: Subjects were 18--35 years old and had no history of panic attacks and no current DSM-IV diagnosis other than simple or social phobia. Those at high risk for panic disorder (HR-P) (n = 46) had a first-degree relative with treated panic disorder. Low-risk control subjects (LR-C) (n = 39) had no first-degree relative with panic disorder. Respiratory measurements were taken continuously while subjects breathed room air through an attached mask for 3 min and, subsequently, while they breathed a 5% CO(2)/air mixture for an additional 3 min. RESULTS: HR-P subjects did not differ from control subjects by group means of the principal measure of respiratory response, changes in minute volume (MV) during CO(2) inhalation. However, these values assumed clearly different distributions in the two groups. Fifteen (32.6%) of the HR-P subjects showed a paradoxical decrease in MV while breathing CO(2) and six (13%) displayed a particularly rapid increase in MV. Only one (2.6%) of the control subjects had a negative MV slope and none had a high value [chi(2)(1) = 12.3, p <.001, p =.021, Fisher exact test, respectively]. Though the subjects with high MV increases also described greater increases in anxiety after breathing CO(2), a regression analysis indicated that the MV increase was the more important in discriminating high-risk from control subjects. CONCLUSIONS: These results suggest that respiratory sensitivity to CO(2) inhalation is operative in the familial transmission of panic disorder.     

Modulation by muscarinic antagonists of the response to carbon dioxide challenge in panic disorder

BACKGROUND: Panic attacks can be induced in persons with panic disorder by inhalation of carbon dioxide. Hypercapnia also elicits a reflex hyperventilation, which is controlled in part by cholinergic mechanisms. This study investigated whether the exaggerated response to carbon dioxide in panic disorder (PD) can be modulated by antagonists of muscarinic cholinergic receptors. METHODS: Twelve patients with PD received biperiden hydrochloride (a muscarinic antagonist that crosses the blood-brain barrier), pirenzepine hydrochloride (a muscarinic antagonist that does not cross the blood-brain barrier), or placebo 2 hours before a 35% carbon dioxide-65% oxygen respiratory challenge (vs air as a placebo) on 3 separate days, in a double-blind, random crossover design. RESULTS: According to patients' self-ratings of subjective anxiety, inhalation of the carbon dioxide/oxygen mixture provoked a significant and intense response after treatment with pirenzepine and placebo. After biperiden treatment, however, hypercapnia elicited a response profile similar to that elicited by air, whereby subjective anxiety remained similar to preinhalation levels. CONCLUSIONS: Consistent with the hypothesis of the study, a centrally active muscarinic antagonist can block the response to carbon dioxide commonly observed in subjects with PD.     

A long-term prospective evaluation of first-degree relatives of panic patients who underwent the 35% CO2 challenge.

BACKGROUND: This follow-up study investigated the potential priming effect of the 35% CO2 challenge on the development of anxiety disorders and/or panic attacks in healthy first-degree relatives of panic patients across a period of 3-4 years subsequent to the challenge. METHODS: Thirty-one relatives who underwent the 35% CO2 challenge 3-4 years before and 14 relatives, free from psychiatric diagnoses in the same period, were directly reevaluated for the presence of anxiety disorders and panic attacks. RESULTS: None developed anxiety disorders and only 1, among relatives previously tested with the 35% CO2 challenge, reported sporadic panic attacks. CONCLUSIONS: The 35% CO2 challenge is a safe research paradigm in the investigation of healthy subjects with a familial vulnerability to panic, and CO2 hypersensitivity might be considered a trait marker of an underlying familial vulnerability to panic disorder.