Sensitivity to carbon dioxide in subjects with a single lifetime panic attack: possible clinical "bedside" predictive test for panic disorder after a first attack

There is currently no way of knowing whether a patient who has recently had a single panic attack has incipient panic disorder. Sensitivity to carbon dioxide (CO2) is lower in healthy volunteers than in panic disorder patients. If this is also true of people who experience a single lifetime panic attack, it could be used as a prognostic test. Subjects with a single lifetime panic attack and subjects with panic disorder received an inhalation of 35% CO2. Subjects completed the panic symptoms scale (PSS), and also stated whether they considered that they had experienced an attack. None of 14 subjects with a single lifetime panic attack, compared to 7 of 17 subjects with panic disorder (P=.009), had an attack. The PSS also distinguished between the groups. The 35% CO2 challenge warrants further investigation as a predictive test after a first panic attack.     

Hypothalamic-pituitary-adrenal axis function following a 35% CO2 inhalation in healthy volunteers

RATIONALE: The hypothalamic-pituitary-adrenal axis (HPA axis) is a central component of the brain's neuroendocrine response to stress. The extent of increase in cortisol secretion, provides an index of the HPA axis activity, and in this way, objectively reflects perceived stress. In healthy subjects, the 35% CO(2) inhalation does hardly induce stress, as expressed in anxiety. However, inconsistent results have been found in studies investigating the cortisol response following CO(2) inhalation. Clarity has to be reached about the normal reaction to this challenge, especially because this model is still a very valuable method to study central aspects of panic. OBJECTIVES: The present study aimed to test the hypothesis that a single breath of 35% CO(2) would not induce cortisol release in healthy volunteers. METHODS: In the current study, 20 healthy subjects underwent both a 35% CO(2) and a placebo inhalation in a randomised, single blind fashion. Cortisol levels were determined in saliva samples, taken at regular intervals. RESULTS: No differences were found between the CO(2) and the placebo condition. In both conditions a significant time effect was found, which can be subscribed to normal variation in the circadian rhythm. Furthermore, only modest subjective anxiety scores were found in the CO(2) condition. CONCLUSIONS: These results provide biological evidence for the hypothesis that healthy subjects are not affected by the 35% CO(2) challenge in a clinically significant way. Characteristic, PD patients react much stronger to the inhalation. Thus, in addition to psychological parameters, healthy subjects also constitute an ideal comparison group with regard to endocrinological parameters.     

Basilar artery blood flow velocity changes in patients with panic disorder following 35% carbon dioxide challenge

PURPOSE: We compared the mean basilar artery blood flow velocity (BABFV) between patients with panic disorder and healthy subjects both at rest and immediately following carbon dioxide (CO(2)) challenge, and examined the effects of treatment on BABFV. METHODS: Twenty four patients with panic disorder with or without agoraphobia and 12 healthy comparison subjects were studied. Visual Analog Anxiety Scale was used to evaluate the anxiogenic effect of 35% CO(2) inhalation. Mean BABFV was monitored using transcranial Doppler ultrasonography at rest and 10, 20, 30, 60, 90, 120 s after 35% CO(2) challenge both before and after four weeks treatment with paroxetine. RESULTS: The hemodynamic response pattern of basilar artery to CO(2) inhalation was significantly different between two groups. CO(2) rapidly triggered blood flow velocity in basilar artery amongst panic patients but not in healthy comparisons. The mean time to normalization of BABFV was significantly longer in panic patients. Four weeks of treatment with paroxetine led to a significantly reduced mean BABFV after 35% CO(2) inhalation in comparison with pretreatment. CONCLUSIONS: Patients with panic disorder had impaired cerebral regulatory mechanisms observed as a change in response characteristics in BABFV in response to CO(2) inhalation. Treatment with paroxetine reduced the increase of BABFV seen in patients after the CO(2) challenge.     

Reactivity to a 35% CO2 challenge in healthy first-degree relatives of patients with panic disorder.

BACKGROUND: The effects of a 35% CO2 challenge were examined in healthy first-degree relatives of panic disorder patients and in healthy control subjects matched for age and gender. METHODS: One single inhalation of a 35% CO2/65% O2 challenge was administered to 50 first-degree relatives of panic disorder patients and 50 control subjects. RESULTS: The first-degree relatives were more reactive to the 35% CO2 challenge than the control subjects. CONCLUSIONS: These findings indicate that being a member of a family with a panic disorder patient is, in itself an important factor in CO2 hypersensitivity among subjects who have never experienced a panic attack. Both panic disorder patients and their first-degree relatives have a tendency to be more reactive to the CO2 challenge.     

The influence of ethanol infusion on the effects of 35% CO2 challenge. A study in panic disorder patients and healthy volunteers.

Alcohol and panic disorders co-occur at a rate that exceeds chance significantly. Early experimental work suggests that alcoholic subjects, compared to non-alcoholics, are less sensitive to sodium lactate and that alcohol intake reduces the response to a 35% CO(2) challenge in Panic Disorder patients. The present study documents the direct pharmacological effect of ethanol infusion on CO(2) induced panic. METHODS: According to a placebo-controlled, double-blind, randomized, cross-over design 10 drug free panic disorder patients and 16 healthy volunteers underwent a 35% CO(2) challenge after intravenous infusion of a moderate dose of ethanol on one test day and of placebo on another test day. RESULTS: Compared to the placebo condition, the effect of the CO(2) challenge was significantly smaller after ethanol infusion (P = 0.041). DISCUSSION: A moderate dose of ethanol decreased the response to a 35% CO(2) without inducing pre challenge sedation. CONCLUSION: The results comfort earlier findings of a direct pharmacological effect of ethanol on panic.     

Inhalation of 35% CO(2) results in activation of the HPA axis in healthy volunteers

BACKGROUND: The hypothalamo-pituitary-adrenal (HPA) axis is a major stress responsive system in humans. Although there are numerous ways of testing responsiveness of the HPA in experimental animals, this is much more difficult in man. Hypercapnea is a very stressful stimulus for humans and has been used as an anxiogenic probe in psychiatric patients. We have now investigated whether the simple challenge of a single 35% inhalation of CO(2) activates the neuroendocrine system as evidenced by changes in HPA activity, as well as cardiovascular and subjective responses, in healthy volunteers.METHODS: Fourteen healthy male volunteers were recruited. They underwent single vital capacity inhalation of room air and 35% CO(2), in a single blind fashion. Neuroendocrine, cardiovascular and subjective fear measures were taken at regular intervals.RESULTS: CO(2) inhalation produced significant activation of the HPA axis in all subjects, as measured with plasma cortisol. Heart rate was decreased and systolic blood pressure was significantly increased shortly after the inhalation of CO(2). The subjects reported short-lived symptoms of fear with the experimental gas.CONCLUSIONS: Single vital capacity inhalation of 35% CO(2) activated the HPA axis in healthy volunteers. It also had a significant cardiovascular and psychological (anxiogenic) effect, as expected from previous published studies. The test is potentially useful in studying the responsivity of the HPA axis in health and disease.     

Comparison of 35% carbon dioxide reactivity between panic disorder and eating disorder

Patients with panic disorder (PD) are hyperreactive to carbon dioxide (CO(2)), but the specificity of this characteristic to PD is controversial. Anxiety and phobic symptomatology are common to both panic and eating disorders (ED). To investigate the specificity of CO(2) hyperreactivity to PD, the responses to inhalation of a 35% CO(2) and 65% oxygen (O(2)) gas mixture were assessed. Reactions to 35% CO(2) challenge were compared among three groups of age- and sex-matched subjects: 14 patients with ED, 14 patients with PD, and 14 healthy controls (HC). A double-blind, randomized, crossover design was used. Only patients with PD showed a strong reaction to 35% CO(2), while patients with ED and HC did not react significantly. The results support the specificity of CO(2) hyperreactivity to 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.     

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.     

Serotonin regulation of the human stress response

Acute tryptophan depletion (ATD) is a technique that has been used to evaluate the effects on humans of acutely reducing serotonin neurotransmission. We have developed a model using a single breath of 35% CO(2) that activates the hormonal axis and produces autonomic and behavioural arousal, thus modelling a stress response. This study combines ATD and single breath 35% CO(2) inhalation to study stress responses in volunteers. A randomised, double-blinded, placebo-controlled, cross-over trial involving 14 healthy adult volunteers aged between 18 and 65 years was undertaken. Subjects underwent double-blind tryptophan depletion over 2 days and were then crossed over 1 week later. During each study day, at the time of peak depletion, participants were single blinded to receive a single breath of 35% CO(2) or air. This was followed 40 min later by the other gas. Psychological outcomes were assessed with the Spielberger State Anxiety Inventory (SSAI), Visual Analogue Scales (VAS), Panic Inventory (PI), Panic and Agoraphobia Scale (PSI) and Beck Depression Inventory (BDI). Physiological outcome was measured by serial plasma cortisol, prolactin and tryptophan levels, pulse and blood pressure. Tryptophan depletion did not exacerbate 35% CO(2) inhalation effects on anxiety symptoms. Single breath CO(2) robustly increased plasma cortisol levels in comparison to an air inhalation; this was less certain for prolactin levels. ATD influenced the HPA axis (associated with higher cortisol levels), apparently independent of CO(2) or air inhalation stressors. ATD and 35% CO(2) inhalation both induced a pressor response and bradycardia in these normal volunteers. Thirty-five percent CO(2) inhalation and ATD independently activate the human stress response, but do not appear to produce synergistic effects when combined, at least for the conditions produced in this study.     

Effect of CCK-4 on a 35% carbon dioxide challenge in healthy volunteers

1. 1. The purpose of this study was to determine whether a subthreshold dose of CCK-4 would enhance the vulnerability of healthy subjects to a 35% carbon dioxide challenge.

2. 2. 27 subjects, with no prior or present psychiatric disorder and in good physical condition were challenged with a vital capacity breath of a 35% carbon dioxide mixture, immediately after an intravenous injection of 5 μg CCK-4 or placebo, according to a random order double blind crossover design.

3. 3. Subjects reported significantly less panic symptoms upon carbon dioxide after premedication with CCK-4 than after placebo.

4. 4. Both CCK-4 and carbon dioxide may act on the same neuronal pathways, but seem to inhibit rather than potentiate each other effects.

     

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.     

Psychological features of subjects with idiopathic environmental intolerance

OBJECTIVES: Idiopathic environmental intolerance (IEI) is associated with unexplained symptoms attributed to non-noxious levels of environmental substances. Clinically, some of the symptoms of IEI overlap with those of panic disorder (PD). We have recently reported a link between IEI and panic responses to a single inhalation of 35% carbon dioxide (CO(2)), a reliable panic induction challenge. This study assessed depression, stress, anxiety, and agoraphobic symptoms among IEI subjects from our previous study versus healthy controls. METHODS: Thirty-six IEI and 37 control subjects with no preexisting psychiatric history were compared on self-report psychological questionnaires. RESULTS: IEI subjects scored significantly higher than controls on the Agoraphobic Cognitions Questionnaire (ACQ), Depression Anxiety Stress Scales (DASS), and Mobility Inventory for Agoraphobia (MI) (Student's t, P<.05). CONCLUSIONS: IEI subjects represent a group with morbidity significantly higher than a control population but less than what would be expected for a clinical psychiatric population.     

Ventilatory physiology of patients with panic disorder

Thirty-one patients with DSM-III panic disorder or agoraphobia with panic attacks, 13 normal controls, and 12 patients with other anxiety disorders were studied during ventilatory challenge with room air hyperventilation and 5% carbon dioxide inhalation. Patients also underwent sodium lactate infusion. Among the patients with panic disorder, 58% panicked with sodium lactate, 39% with 5% CO2, and 23% with room air hyperventilation. Of the other patients, four panicked with sodium lactate, none with 5% CO2, and one with room air hyperventilation. One normal control panicked with both sodium lactate and 5% CO2. Panic with CO2 was associated with an exaggerated ventilatory response and increases in plasma norepinephrine level and diastolic blood pressure. Patients with panic disorder may have hypersensitive CO2 receptors that, when triggered, evoke a subjective panic associated with an exaggerated ventilatory response and consequent hypocapnic alkalosis.     

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.     

Panic disorder: the role of the balance system

Experimental evidences suggest that Panic Disorder (PD) is characterized by abnormalities in respiratory and vestibular functions. We studied balance system function in patients with PD and its relationships with CO(2) reactivity and clinical characteristics. Nineteen patients with PD with/without agoraphobia underwent static posturography and the 35% CO(2) challenge. The severity of clinical symptomatology was measured by standardized psychometric scales. Patients were free of psychotropic medications during the 2 weeks before the study. Different investigators blind to each other carried out the CO(2) challenge, static posturography and clinical assessment. Nineteen age and sex-matched healthy controls underwent static posturography. Body sway velocity and length were significantly higher in panic patients than in controls and patients showed high percentages of abnormal scores. Patients with two or more abnormal scores on static posturography were significantly more agoraphobic than those with less than two. Abnormal posturography scores under the eyes-opened was related to high anticipatory anxiety, whereas those under eyes-closed was related to phobic avoidance. Symptomatological reactivity to CO(2) was significantly correlated to abnormal functions of the balance system in the eyes-closed condition. Our findings suggest that (1) many patients with PD (5-42%) have abnormalities in their balance system function compared with healthy controls (0-5%), (2) symptomatological reactivity to CO(2) and balance system function in patients with PD are correlated only in the eyes-closed condition and (3) there is a significant link between agoraphobic avoidance and subclinical abnormal function of the balance system network.     

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.     

Effects of experimental panic on neuroimmunological functioning

OBJECTIVE: Psychoimmunological research in panic disorder (PD) so far focussed on single time point evaluation in resting conditions. No robust evidence for changes in the immune system was found using this method. However, PD is characterized by the occurrence of unexpected panic attacks (PAs). The current research focuses on cytokine and acute phase protein (APP) levels and mitogen-induced cytokine secretion following 35% CO(2) inhalation-induced panic. METHODS: Eighteen PD patients and 18 matched healthy control subjects underwent both a placebo and a 35% CO(2) inhalation on separate days. Blood samples for cytokine and APP determination were taken before and after the inhalation. In addition to serum determination, whole blood samples were cultured and stimulated with mitogens for assessment of the functional capacity of the immune system. RESULTS: The 35% CO(2) inhalation induced significantly higher levels of anxiety in PD patients as compared to the control subjects, but no differences in immune parameters were found, either in basal conditions or after experimental panic induction. CONCLUSION: In our sample we do not find any changes in serum levels or functional capacity of several immunological parameters in the experimentally provoked PAs. Similar results have been found in social phobia, whereas in other affective disorders such as depression and posttraumatic stress disorder, immune changes are evident. Changes seem to coincide with alterations in hypothalamic-pituitary-adrenal (HPA) axis function. Therefore, the bidirectional communication pathway between the immune system and the HPA axis might play a role in some affective disorders, but it does not specifically seem to be involved in the etiology of PD.     

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.     

Double-blind acute clonazepam vs. placebo in carbon dioxide-induced panic attacks

The inhalation of 35% carbon dioxide has consistently been shown to provoke panic attacks in panic disorder patients. We aim to determine if an acute dose of clonazepam (2 mg) attenuates the panic attacks induced by an inhalation of 35% carbon dioxide in panic disorder. Twenty-two panic disorder patients who had been drug-free for 1 week participated in a carbon dioxide challenge test 1 h after a dose of either 2 mg of clonazepam or placebo with a randomized double-blind method. Also in a double-blind design during the tests the patients inhaled either atmospheric compressed air ('placebo control') or the carbon dioxide mixture. All patients participated in both tests which were done with a 20-min interval. Immediately before and after the inhalation, the anxiety levels and the symptoms of panic were always assessed. In the clonazepam group (n=11) two patients (18.2%) had a mild panic attack and in the placebo group (n=11) nine patients (81.8%) had a moderate to severe panic attack in the CO(2) challenge test. No patient had panic attacks during inhalation of atmospheric compressed air although anticipatory anxiety levels tended to be higher than in the CO(2) tests. After the CO(2) test anxiety levels were significantly greater in the CO(2) group (three-way ANOVA with Geisser-Greenhouse adjustments, F(31.92,1.86)=17.15, d.f.=7, P=0.013). Although a small sample was studied, the findings suggest the efficacy of an acute dose of clonazepam in attenuating panic attacks induced by carbon dioxide inhalation.