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CO 2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO 2 , and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO 2 /pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO 2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO 2 , males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO 2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO 2 exposure in mice., Competing Interests: Declaration of competing interest The authors have no competing interests to declare and have no relevant financial or non- financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Panic disorder (PD) pathophysiology is very heterogeneous, and the discrimination of distinct subtypes could be very useful. A subtype based on respiratory symptoms is known to constitute a specific subgroup. However, evidence to support the respiratory subtype (RS) as a distinct subgroup of PD with a well-defined phenotype remains controversial. Studies have focused on characterization of the RS based on symptoms and response to CO2. In this line, we described clinical and biological aspects focused on symptomatology and CO2 challenge tests in PD RS. The main symptoms that characterize RS are dyspnea (shortness of breath) and a choking sensation. Moreover, patients with the RS tended to be more responsive to CO2 challenge tests, which triggered more panic attacks in this subgroup. Future studies should focus on discriminating respiratory-related clusters and exploring psychophysiological and neuroimaging outcomes in order to provide robust evidence to confirm RS as a distinct subtype of PD.

Heart rate variability (HRV) and end tidal CO2 (ETCO2) in relation to treatment response have not been studied in Latino populations or in comorbid asthma and panic disorder (PD). An extension of previously published research, the current study explored psychophysiological variables as possible mediators of treatment response. Latino treatment completers (N = 32) in the Bronx with asthma-PD received either Cognitive-Behavioral Psychophysiological Therapy (CBPT) or Music Relaxation Therapy (MRT). CBPT included HRV-biofeedback (HRVB); in-the-moment heart rate data to help an individual learn to influence his/her own heart rate. The sample was primarily female (93.8%) and Puerto Rican (81.25%). Treatment groups did not differ on demographics, except for less education in CBPT. The Panic Disorder Severity Scale (PDSS) and Asthma Control Questionnaire (ACQ) assessed changes in symptoms. HRV and ETCO2 were measured at four of eight therapy sessions. Baseline ETCO2 and changes in HRV from first to last of psychophysiology sessions were investigated as mediators of change on ACQ and PDSS. Mixed model analyses indicated in the CPBT group, changes in both asthma control and PD severity were not mediated by changes in HRV. In the CBPT and MRT groups combined, changes in PD severity were not mediated by baseline ETCO2. These findings may be due to the brevity of HRVB in CBPT, multiple treatment components, ETCO2 not directly targeted, and/or unique physiological pathways in Latinos with asthma-PD.

Objective: The objective of this study is to perform a systematic review and meta-analysis on whether patients with panic disorder (PD) and their healthy first-degree relatives have an increased sensitivity to carbon dioxide inhalation test compared to healthy controls (HC) or patients with psychiatric disorders other than panic disorder., Method: The databases of PubMed, EMBASE and PsycNET were searched using Boolean operators "panic AND carbon dioxide" and "panic AND CO2". Selected research articles were classified according to the carbon dioxide concentrations used in testing and the clinical characteristics of the samples. The assumption of heterogeneity across the studies was assessed by chi square based Q and I2 statistics. Publication biases were explored by Begg-Mazumdar's and Egger's tests in addition to funnel graphics. Odds ratios representing effect size of the carbon dioxide inhalation procedure were calculated according to fixed effect and random effect models after obtaining percent weight effects of each study., Results: Meta-Analysis was conducted on 33 research studies that include 2114 participants totally. Participants with PD experienced significantly more frequent panic attacks (PA) compared to HC following in both 5% (OR=14.713, 95% CI 7.532 - 28.739) and 35% carbon dioxide inhalation (OR=11.507, 95% CI 7.775 - 17.031). HC who have a first-degree relative with PD experienced PA approximately 3 times more than HC who have not a first-degree relative with PD (OR=2.658, 95% CI 1.678 - 4.212) following carbon dioxide inhalation test. Participants with PD experienced significantly more frequent PA than the patients with other psychiatric disorders following the carbon dioxide inhalation test (OR = 3.524, 95% CI 1.945 - 6.384)., Conclusion: There is an increased sensitivity of carbon dioxide inhalation in patients with PD and their healthy first-degree relatives. The role and possible mechanisms of carbon dioxide in etiology and physiopathology of PD should be studied extensively.

Heightened concentrations of CO 2 in inhaled air provoke temporary acidification of the brain, followed by compensatory hyperventilation and increased arousal/anxiety. These responses are likely to map a basic, latent general alarm/avoidance system that is largely shared across mammals, and are sources of individual differences. By showing paroxysmal respiratory and emotional responses to CO 2 challenges, humans with panic and separation anxiety disorders lie at one extreme of the distribution for CO 2 sensitivity. This is also a developmental trait, sensitive to interference with parental cares. By sharing CO 2 sensitivity with humans, rodents constitute a valuable resource to model panic and separation anxiety in the laboratory. Advantages of modeling CO 2 sensitivity in rodents include non-inferential measurements (e.g. respiratory readouts) as proxies for human conditions, unbiased investigation of gene-environment interplays, and flexible availability of tissues for mechanistic studies. Data in humans and animals such as those reported in this issue of Neuroscience begin to reveal that CO 2 -driven behavioral responses stem from anatomo-physiological systems that are relatively separated from those subserving general dispositions to anxiety. This supports the notion that sensitivity to suffocative stimuli and ensuing human panic are significantly independent from trait/cognitive anxiety, and corroborates newer conceptualizations that distinguish between fear and anxiety circuitries., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Inhalation of carbon dioxide (CO 2 ) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO 2 reliably evokes panic attacks. Sensitivity to CO 2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO 2 are therefore relevant. In the current study we investigated CO 2 -evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO 2 -chemosensitivity. Behavioral responsivity to CO 2 inhalation varied between strains. CO 2 -evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO 2 -evoked rearing and grooming behaviors. Exposure to CO 2 did not produce conditioned behavioral responses upon re-exposure to CO 2 context in any strain. Reduced TPH-2-positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal gray (VLPAG) subdivision in CO 2 -sensitive strains. Conversely, DβH-positive cell counts within the LC were significantly higher in CO 2 -sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO 2 -sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO 2 -vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO 2 -sensitivity in the development of panic and anxiety disorders., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Self-reported anxiety, and potentially physiological response, to maintained inhalation of carbon dioxide (CO 2 ) enriched air shows promise as a putative marker of panic reactivity and vulnerability. Temporal stability of response systems during low-dose, steady-state CO 2 breathing challenge is lacking. Outcomes on multiple levels were measured two times, one week apart, in 93 individuals. Stability was highest during the CO 2 breathing phase compared to pre-CO 2 and recovery phases, with anxiety ratings, respiratory rate, skin conductance level, and heart rate demonstrating good to excellent temporal stability (ICCs≥0.71). Cognitive symptoms tied to panic were somewhat less stable (ICC=0.58) than physical symptoms (ICC=0.74) during CO 2 breathing. Escape/avoidance behaviors and DSM-5 panic attacks were not stable. Large effect sizes between task phases also were observed. Overall, results suggest good-excellent levels of temporal stability for multiple outcomes during respiratory stimulation via 7.5% CO 2 ., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.

Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The carbon dioxide test--a vital capacity breath of air containing 35% carbon dioxide (CO(2))--provokes panic attacks in many individuals with panic disorder (PD). It has thus been extensively used as an experimental model of panic and less frequently as a clinical method of provoking symptoms for interoceptive exposure treatment. Recently, stress researchers have suggested another use for the CO(2) test: that of an acute physiological stressor indexing the human stress response. The purpose of this review is to synthesize findings about the effects of the CO(2) test from both the panic and stress literatures in order to advance understanding about this increasingly popular test. Both panic and stress researchers have examined the fleeting effects of the CO(2) test, finding that the test engenders transient breathlessness, dizziness, and minor anxiety in most participants and panic attacks in those with or at risk for PD. Physiological measurements after the test indicate a brief homeostatic disruption in many bodily systems, including increased respiration, systolic blood pressure, and noradrenaline, and decreased heart rate. Most studies indicate increased cortisol. Possible benefits of integrating findings from the panic and stress research lines, given their common use of the CO(2) test, are discussed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

It has been well established that the inhalation of Carbon Dioxide (CO2) can induce in humans an emotion closely replicating spontaneous panic attacks, as defined by current psychiatry nosology. The purpose of this review is to provide a critical summary of the data regarding CO2's psychopharmacological properties and underlying mechanisms. The authors review the literature on the human and animal response for the exposure of exogenous CO2 focusing on five points of interest: 1) the early history of the use of CO2 as an anesthetic and therapeutic agent, 2) the subjective effects of breathing CO2 at different concentrations in humans, 3) the use of CO2 in experimental psychiatric research as an experimental model of panic, 4) the pharmacological modulation of CO2-induced responses, and 5) the putative neurobiological mechanisms underlying the affective state induced by CO2. The authors conclude with an evolutionary-inspired notion that CO2 might act as an agent of a primal emotion serving a homeostatic function, in the control of respiration and acid-base balance.

Background and Objectives: The present investigation examined mask disturbance behavior in the context of a biological challenge., Method: Participants included 128 adults (63.3% women; M(age) = 23.2, SD = 8.9) who underwent a 10% carbon dioxide-enriched air challenge., Results: Mask disturbance behavior, including complete or partial mask removal, was common during the challenge. Moreover, mask removal behavior during the challenge was significantly related to a greater increase in anxiety pre- to post-challenge, as well as greater levels of self-reported avoidance of a future challenge administration. However, mask touching and lifting behaviors were not related to other challenge criterion variables., Limitations: The current study consisted primarily of young adults and did not include individuals with a panic disorder diagnosis. Replication and extension of the current findings is recommended., Conclusions: Results suggest that mask removal behavior during the challenge may represent a possible behavioral marker of panic-relevant risk, although further work is necessary to determine its usefulness as a challenge measure., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO₂, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO₂ were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1mg/kg), and alprazolam (0.3mg/kg) injections. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO₂, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO₂ were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO₂, which might be related to CO₂ induced panic., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Panic disorder is a common and disabling illness for which treatments are too frequently ineffective. Greater knowledge of the underlying biology could aid the discovery of better therapies. Although panic attacks occur unpredictably, the ability to provoke them in the laboratory with challenge protocols provides an opportunity for crucial insight into the neurobiology of panic. Two of the most well-studied panic provocation challenges are CO(2) inhalation and lactate infusion. Although it remains unclear how these challenges provoke panic animal models of CO(2) and lactate action are beginning to emerge, and offer unprecedented opportunities to probe the molecules and circuits underlying panic attacks. Both CO(2) and lactate alter pH balance and may generate acidosis that can influence neuron function through a growing list of pH-sensitive receptors. These observations suggest that a key to better understanding of panic disorder may He in more knowledge of brain pH regulation and pH-sensitive receptors.

We have previously developed a putative model of generalized anxiety disorder in healthy volunteers using a 20-minute 7.5% carbon dioxide (CO(2)) inhalation challenge. The aim of this study was to validate the 7.5% CO(2) paradigm by assessing its effects in patients with generalized anxiety disorder in a test-retest design. Twelve medication-free generalized anxiety disorder patients attended our lab for two study days. On each study day placebo (compressed air) and 7.5% CO(2) mixture were randomly administered over 20 min, at least 30 min apart, in a single blind, randomized, placebo-controlled cross-over design. Subjective ratings, cardiovascular measures and cortisol levels were collected throughout. CO(2) challenge significantly increased ratings for anxiety and other subjective symptoms associated with generalized anxiety disorder, compared with air. It also significantly increased systolic blood pressure on day 2, indicating increased autonomic arousal. There was no change between the two test days in mean anxiety rating scores, and there also appeared to be a correlation for individual scores on a number of the subjective measures. In conclusion, 20 min of 7.5% CO(2) gas inhalation increases anxiety responses in patients with generalized anxiety disorder, and this is reliable over time.

Inhalation of carbon dioxide (CO₂) enriched air triggers anxiety in panic disorder (PD) patients, which is often interpreted as a sign of biological vulnerability. However, most studies have not measured respiration in these tasks. We compared patients with PD (n=20) and social phobia (SP, n=19) to healthy controls (n=18) during eight inhalations of 20% CO₂, preceded and followed by two inhalations of room air, while continuously measuring subjective anxiety and dyspnea as well as autonomic and respiratory variables. PD patients showed increased reactivity and delayed recovery during CO₂ inhalations for most measures. Unlike both other groups, the PD group's tidal volume responses did not habituate across CO₂ inhalations. However, PD patients did not differ from SP patients on most other measures, supporting a continuum model of CO₂ sensitivity across anxiety disorders. Both patient groups showed continued reactivity during the last air inhalations, which is unlikely to be due to a biological sensitivity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Individuals with panic disorder and those at high risk for panic disorder due to a positive family history seem to have elevated sensitivities to the panicogenic effects of carbon dioxide (CO2) inhalation as well as abnormal ventilatory responses to low doses of CO2 exposure. Many reports have described a reduction in anxiety responses in individuals with panic disorder after a brief treatment with a variety of medications effective in the treatment of panic disorder, but few of these have used placebo control., Methods: Thirty-two unmedicated individuals who had either a past history of panic attacks or a family history of treated panic disorder and who demonstrated, at baseline, a panic attack after either a single breath of 35% CO2 or 3 minutes of exposure to 5% CO2 or a decline in minute volume during 3 minutes of exposure to 5% CO2 were randomized to 2-week trials of escitalopram at 10 mg daily or placebo and, after a 1-week washout, to a 2-week trial of the alternate condition., Results: Placebo and escitalopram conditions did not differ by changes in anxiety responses to high-dose, single-breath, or low-dose continuous-breathing CO2 exposures. Ventilatory abnormalities were no more likely to resolve with escitalopram than with placebo. Self-ratings of anxiety and depressive symptoms showed little change over time with either escitalopram or placebo., Conclusions: Escitalopram did not produce greater changes than placebo in panic responses or in ventilatory abnormalities seen during CO2 exposure. Future studies concerning the effects of antidepressants on responses to CO2 challenge should use a placebo-controlled design.

Background: CO(2) respiration stimulates both anxiety and dyspnea ("air hunger") and has long been used to study panic vulnerability and respiratory control. High comorbidity with panic attacks suggests individuals with bipolar disorder may also mount a heightened anxiety response to CO(2). Moreover, problems in the arousal and modulation of appetites are central to the clinical syndromes of mania and depression; hence CO(2) may arouse an abnormal respiratory response to "air hunger"., Methods: 72 individuals (34 bipolar I, 25 depressive and bipolar spectrum, 13 with no major affective diagnosis) breathed air and air with 5% CO(2) via facemask for up to 15 min each; subjective and respiratory responses were recorded., Results: Nearly half the subjects diverged from the typical response to a fixed, mildly hypercapneic environment, which is to increase breathing acutely, and then maintain a hyperpneic plateau. The best predictors of an abnormal pattern were bipolar diagnosis and anxiety from air alone. 25 individuals had a panic response; panic responses from CO(2) were more likely in subjects with bipolar I compared to other subjects, however the best predictors of a panic response overall were anxiety from air alone and prior history of panic attacks., Limitations: Heterogeneous sample, liberal definition of panic attack., Conclusion: Carbon dioxide produces abnormal respiratory and heightened anxiety responses among individuals with bipolar and depressive disorders. These may be due to deficits in emotional conditioning related to fear and appetite. Although preliminary, this work suggests a potentially useful test of a specific functional deficit in bipolar disorder.

Panic disorder (PD) patients usually react with more self-reported distress to voluntary hyperventilation (HV) than do comparison groups. Less consistently PD patients manifest physiological differences such as more irregular breathing and slower normalization of lowered end-tidal pCO(2) after HV. To test whether physiological differences before, during, or after HV would be more evident after more intense HV, we designed a study in which 16 PD patients and 16 non-anxious controls hyperventilated for 3 min to 25 mmHg, and another 19 PD patients and another 17 controls to 20 mmHg. Patients reacted to HV to 20 mmHg but not to 25 mmHg with more self-reported symptoms than controls. However, at neither HV intensity were previous findings of irregular breathing and slow normalization of pCO(2) replicated. In general, differences between patients and controls in response to HV were in the cognitive-language rather than in the physiological realm.

Objective: Posttraumatic stress disorder (PTSD) and panic disorder (PD) are two anxiety disorders with prominent psychophysiological symptoms. The PTSD criterion of persistent hyperarousal suggests autonomic dysregulation, and the disorder has been associated with elevated heart rate. In contrast, PD has been associated with respiratory abnormalities such as low end-tidal Pco(2). An integrated analysis of automatic and respiratory function in a direct comparison of these anxiety disorders is currently lacking., Methods: Electrodermal, cardiovascular, and respiratory psychophysiology was examined in 23 PTSD patients, 26 PD patients, and 32 healthy individuals at baseline and during threat of shock., Results: At baseline, the PTSD patients, in contrast to the other two groups, were characterized by attenuated parasympathetic and elevated sympathetic control, as evidenced by low respiratory sinus arrhythmia (a measure of cardiac vagal control) and high electrodermal activity. They also displayed elevated heart rate and cardiovascular sympathetic activation in comparison with healthy controls. PD patients exhibited lower Pco(2) (hypocapnia) and higher cardiovascular sympathetic activation compared with healthy controls. PTSD patients, but not PD patients, sighed more frequently than controls. During the threat of shock phase, the PTSD group demonstrated blunted electrodermal responses., Conclusions: Persistent hyperarousal symptoms in PTSD seem to be due to high sympathetic activity coupled with low parasympathetic cardiac control. Respiratory abnormalities were also present in PTSD. Several psychophysiological measures exhibited group-comparison effect sizes in the order of 1.0, supporting their potential for enhancing differential diagnosis and possibly suggesting utility as endophenotypes in genetic studies of anxiety disorders.

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.

Our aim was to describe the clinical features of 35% CO2-induced panic attacks in patients with panic disorder (PD) (Diagnostic and Statistical Manual and Mental Disorders, Fourth Edition) and compare them with the last spontaneous panic attack in patients with PD who had not had a panic attack after the 35% CO2 challenge test. We examined 91 patients with PD submitted to the CO2 challenge test. The test consisted of exhaling as fully as possible, took a fast vital capacity breath, held their breath for 8 seconds, exhaled, and then repeated the fast vital capacity breath, again holding for 8 seconds. The patients inhaled the 35% CO2/65% O2 mixture or atmospheric compressed air, randomly selected in a double-blind design. Scales were applied before and after the test. A total of 68.1% (n = 62) patients with PD had a panic attack (responders) after the CO2 test (chi2(1) = 25.87, P = .031). The last spontaneous panic attack and the symptom profile from the patients with PD who had not had a panic attack after the test (n = 29, 31.9%) were described to compare. The responders had more respiratory symptoms (chi2(1) = 19.21, P < .001), fulfilling the criteria for respiratory PD subtype (80.6%); the disorder started earlier (Mann-Whitney, P < .001), had a higher familial prevalence of PD (chi2(1) = 20.45, P = .028), and had more previous depressive episodes (chi2(1) = 27.98, P < .001). Our data suggest that there is an association between respiratory PD subtype and hyperreactivity to a CO2 respiratory challenge test. The responders may be a subgroup of respiratory PD subtype with future diagnostic and therapeutic implications.

Patients with panic disorder (PD) show maladaptive coping but the role of coping in the pathogenesis of panic is unclear. This study examined general coping and panic-specific coping as predictors of fear responding to CO2 inhalation. Subjective and physiological responses including panic attacks were assessed in 45 patients with PD and 45 matched nonclinical controls. Measures of coping were the primary predictors used in the analyses. Consistent with other reports, patients with PD reported increased emotion-focused coping and there was an association between emotion-focused coping and subjective reactivity. However, only panic-specific coping predicted panic attacks in response to the CO2 challenge.

The present study is aimed at characterizing the carbon dioxide (CO2) procedure in healthy subjects to achieve reliable provocation of anxiety symptoms. Thirty healthy subjects inhaled in single-blind both compressed air and 7% CO2 mixture. Panic Symptom List (PSLIII-R), Visual Analogue Scale-Anxiety (VAS-A), State Anxiety Inventory (STAI-Y/1), respiratory parameters and skin conductance were measured. 'Responders' were classified depending on PSLIII-R scores after CO2. Twelve out of the 21 'responders' performed a second test to assess test-retest repeatability. In 21 subjects Delta%VAS-A (45.4 +/- 32.1) and PSLIII-R (pre-test 2.3 +/-2.1, post-test 17.5 +/- 8.2) but not STAI-Y/1, significantly increased during CO2 inhalation. Respiratory Rate, Minute Volume, end-Tidal CO2 and skin conductance rose in 'responders'. Repeatability was studied with Bland-Altman plots, revealing mean difference between tests close to 0 for both Delta%VAS-A and PSLIII-R. Among physiologic parameters, end-Tidal CO2 and Respiratory Rate showed good repeatability, with a within-subject CV of 9.2% and 6%, respectively. The challenge produced measurable response in healthy subjects. Good test-retest repeatability was observed in 'responders'. These data indicate that the test can be suitable for testing putative anti-panic or anxiolytic drugs in clinical studies using a within subject, crossover design.

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., (Copyright (c) 2005 Wiley-Liss, Inc.)

Background: A number of studies have shown that patients with panic disorder are more likely to have panic attacks during carbon dioxide inhalation than are normal comparison subjects. Some studies have shown that antipanic medications can reduce the anxiogenic response to carbon dioxide, but none have shown if this is the case for cognitive behavioral therapy or if successful treatment reduces the respiratory physiologic response to carbon dioxide., Methods: Twenty-five patients with panic disorder and 13 normal comparison subjects underwent baseline testing with 5% and 7% carbon dioxide inhalation. The patients were then retested after at least 12 weeks of treatment with either antipanic medication or cognitive behavioral therapy. Comparison subjects were retested after a similar interval., Results: Successful treatment resulted in lower panic rates, and reduced anxiogenic response. Treatment had no effect, however, on the respiratory physiologic response., Conclusions: There is dissociation in treatment response between the subjective and objective responses to carbon dioxide inhalation in panic disorder patients, with the former but not the latter showing positive change. We hypothesize that the strengthening of higher cortical control over subcortical fear-related structures, whether via medication or cognitive behavioral therapy treatment, results in less anxiety and fear in response to provoked symptoms reminiscent of naturally occurring panic.

The inhalation of carbon dioxide (CO2) is commonly used in patients and volunteers as a means of producing anxiety or panic. It is generally believed that patients with panic disorder are more vulnerable to the effects of CO2 than patients with other anxiety disorders or healthy volunteers and there is speculation and debate as to the mechanism for this apparent sensitivity. Recent work from our group has shown that a single inhalation of 35% CO2 activates the hypothalamic-pituitary-adrenocortical (HPA) axis, increases blood pressure (BP) and increases subjective fear responses in healthy volunteers. Correlation analyses reveal a relationship between the changes in BP and the cortisol increase. These findings led us to postulate that a common mechanism may mediate these and the subjective responses to inhalation of CO2. We propose that the noradrenergic system, particularly the locus coeruleus (LC), but including the A1 and A2 cell groups, may be a key mediator of these responses. This article examines the evidence and discusses the results of studies from our laboratory in relation to a neuroanatomical model centring on the LC.

Objective: The present study examines the possible relationships between anxiety sensitivity (AS) and reactivity to the 35% carbon dioxide (CO(2)) challenge in panic disorder (PD)., Methods: One-hundred eight patients with PD underwent the 35% CO(2) challenge and completed the Anxiety Sensitivity Index (ASI). Multiple regression analyses were applied to evaluate the role of AS as a predictor of CO(2)-induced anxiety., Results: Fifty-six patients with PD showed high AS scores, whereas 48 showed medium scores and 4 low scores. ASI scores significantly predicted symptomatological reaction to CO(2) but not subjective induced anxiety., Conclusion: These findings suggest that the fear of anxiety-related bodily sensations was related to the symptomatological reactivity to CO(2) but did not seem to play a crucial role in the modulation of the subjective anxiogenic/panicogenic response to hypercapnia in patients with PD.

The aim of the present study was to verify the sensitivity to the carbon dioxide (CO2) challenge test of panic disorder (PD) patients with respiratory and nonrespiratory subtypes of the disorder. Our hypothesis is that the respiratory subtype is more sensitive to 35% CO2. Twenty-seven PD subjects with or without agoraphobia were classified into respiratory and nonrespiratory subtypes on the basis of the presence of respiratory symptoms during their panic attacks. The tests were carried out in a double-blind manner using two mixtures: 1) 35% CO2 and 65% O2, and 2) 100% atmospheric compressed air, 20 min apart. The tests were repeated after 2 weeks during which the participants in the study did not receive any psychotropic drugs. At least 15 of 16 (93.7%) respiratory PD subtype patients and 5 of 11 (43.4%) nonrespiratory PD patients had a panic attack during one of two CO2 challenges (P = 0.009, Fisher exact test). Respiratory PD subtype patients were more sensitive to the CO2 challenge test. There was agreement between the severity of PD measured by the Clinical Global Impression (CGI) Scale and the subtype of PD. Higher CGI scores in the respiratory PD subtype could reflect a greater sensitivity to the CO2 challenge due to a greater severity of PD. Carbon dioxide challenges in PD may define PD subtypes and their underlying mechanisms.

Objective: To determine the effect of CO2 inhalation on global cerebral blood flow (gCBF) and pCO2-adjusted gCBF in normal subjects and panic disorder patients., Method: Global cerebral blood flow was determined using quantitative [15O] water imaging in normal subjects (n = 12) and panic disorder patients (n = 14) after inhalations of medical grade air and of 35%/65% CO2/O2 mixture, a known inducer of panic. The gCBF was calculated as an area-weighted mean value. The pCO2 -adjusted gCBF values were calculated based on the formula of Reiman et al. [Am. J. Psychiatr. 143 (1986) 469]. Data were analyzed using repeated-measures ANOVA and regression analyses., Results: The pCO2 values did not differ statistically between normals and panic patients. Panic patients exhibited a decrease in gCBF and stable pCO2-adjusted gCBF values in comparisons of AIR and CO2 inhalations, whereas normals exhibited stable gCBF and increasing pCO2-adjusted gCBF values., Conclusions: Patients with panic disorder, especially when symptomatic, exhibited an abnormal pattern in gCBF response to provocation.

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.

Characteristic features of the panic patients is the increased sensitivity to the CO2. Respiratory pattern abnormalities such as prolonged apnea, diminished ventilatory responsiveness to hypercarbia have been observed in infants at risk for SIDS. Treating the panic attack the SSRI preparations proved to be suitable. Serotonin antagonists effect preventing SIDS is suggested.

Background: Inhalation of carbon dioxide (CO(2)) has been shown to produce more anxiety in patients with panic disorder (PD) than in healthy comparison subjects or patients with most other psychiatric illnesses tested, although premenstrual dysphoric disorder (PMDD) may be an exception. Several reasons have been proposed to explain CO(2) breathing effects in PD. We examined differences in respiratory response to CO(2) breathing in 4 groups to address these issues., Methods: Patients with PD (n = 52), healthy controls (n = 32), patients with PMDD (n = 10), and patients with major depression without panic (n = 21) were asked to breathe 5% and 7% CO(2). Continuous measures of respiratory physiological indices were made., Results: Carbon dioxide breathing produced the expected increases in all 4 respiratory variables measured. More patients with PD and PMDD had panic attacks than did controls or patients with major depression. Subjects who experienced panic during 5% or 7% CO(2) inhalation had the most extreme increases regardless of diagnostic group. Among patients with PD, baseline end-tidal carbon dioxide levels were significantly lower in those who subsequently had a panic attack during 5% CO(2) breathing than those who did not., Conclusions: Although CO(2) breathing causes a higher rate of panic attacks in patients with PD than other groups (except PMDD), the physiological features of a panic attack appear similar across groups. Once a panic attack is triggered, minute ventilation and respiratory rate increase regardless of whether the subject carries a PD diagnosis. These findings are compatible with preclinical fear conditioning models of anxiogenesis.

Past studies in nonclinical samples have found that suffocation fear, but not a behavioral index of carbon dioxide (CO2) sensitivity (i.e., breath-holding duration), predicts anxious response to CO2 challenge. These associations were examined in individuals with panic disorder while adding more sensitive indices of CO2 sensitivity. Consistent with the earlier studies, the authors found that suffocation fear predicted anxious responding to CO2 challenge but breath-holding duration did not. However, highly precise measures of CO2 sensitivity, not included in earlier studies, did predict anxious challenge responding. These findings support the predictive value and possible etiological relevance of both specific psychological variables and physiological CO2 sensitivity in panic vulnerability. Further work is still needed to determine whether the findings are specific to panic disorder.

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.

1. Studies on the pathogenesis of panic disorder (PD) have concentrated on panic attacks. However, PD runs a chronic or episodic course and panic patients remain clinically unwell between attacks. Panic patients chronically hyperventilate, but the implications of this are unclear. 2. Provocation of panic experimentally has indicated that several biological mechanisms may be involved in the onset of panic symptoms. Evidence from provocation studies using lactate, but particularly carbon dioxide (CO2) mixtures, suggests that panic patients may have hypersensitive CO2 chemoreceptors. Klein proposed that PD may be due to a dysfunctional brain's suffocation alarm and that panic patients hyperventilate to keep pCO2 low. 3. Studies of panic patients in the non-panic state have shown EEG abnormalities in this patient group, as well as abnormalities in cerebral blood flow and cerebral glucose metabolism. These abnormalities can be interpreted as signs of cerebral hypoxia that may have resulted from hyperventilation. 4. Cerebral hypoxia is probably involved in the causation of symptoms of anxiety in sufferers of chronic obstructive pulmonary diseases. By chronically hyperventilating, panic patients may likewise be at risk of exposure to prolonged periods of cerebral hypoxia which, in turn, may contribute to the chronicity of their panic and anxiety symptoms. 5. Chronic hyperventilation may engender a self-perpetuating mechanism within the pathophysiology of PD, a hypothesis which warrants further studies of panic patients in the non-panic state.

Results of an earlier study in healthy volunteers suggest that the serotonergic system is involved in anxiety-related mechanisms. We studied the influence of tryptophan depletion on the response to a 35% carbon dioxide challenge. Twenty-four panic disorder patients received a mixture of amino acids, either with or without tryptophan, under double-blind conditions. There was a significant increase in anxiety as well as in neurovegetative symptoms in the depletion group, compared to the placebo condition. Furthermore, when we compare the results of the placebo group with earlier panic provocation studies, it also seems that a balanced amino acid mixture might have a protective effect against a panic provocation. We conclude that the panic-enhancing effect of tryptophan depletion as well as the potential protective effect of tryptophan administration in panic disorder patients can be explained by the Deakin-Graeff theory of anxiety.

Background: Idiopathic environmental intolerance (IEI) is associated with unexplained physical symptoms, which overlap considerably with those of panic disorder (PD)., Objective: This study tested the hypothesis that patients with symptoms to suggest IEI exhibit features of PD in response to nonnoxious environmental stimuli., Methods: A single-blind, case-control 35% carbon dioxide inhalation challenge was conducted at a university-based occupational health unit with the use of standardized psychologic questionnaires involving 36 patients with IEI and 37 healthy control subjects. The main outcome measures included panic attack symptoms and scores on the Anxiety Sensitivity Index, a measure of panic-related anxiety., Results: Patients with IEI scored significantly higher on the Anxiety Sensitivity Index than control subjects did (P <.05). Significantly more patients with IEI (71%) than control subjects (26%) fulfilled panic attack criteria after carbon dioxide (P <.001). Physiologic responses to the challenge were not significantly different between groups., Conclusions: Results suggest that, similar to patients with PD, patients with IEI display high anxiety sensitivity and in response to carbon dioxide inhalation tend to experience heightened anxiety and panic attacks.

The objectives of this study were to compare continuous subjective and physiological responses of panic disorder patients and normal controls during 5% CO2 inhalation. Psychophysiological responses of panic disorder patients (n = 42) and controls (n = 25) were monitored during baseline (20 min), 5% CO2 inhalation (20 min), and recovery (20 min). The data were compared at baseline and over periods of the experiment using analysis of variance. A subgroup of patients who experienced panic attacks during the CO2 inhalation (n = 12) were significantly different from the other subjects on baseline heart rate and on variability of systolic and diastolic blood pressure, skin conductance, and breathing variability (length and number of breathing pauses and length of breathing cycle variability). Inspection of the data showed that elevation in blood pressure and breathholding were present during some of the panic attacks, suggesting that some attacks may represent a complex psychophysiological response with elements of a "freezing" reaction, well described in animal experiments, which can quickly shift to a "fight/flight" reaction that is usually characterized by an increase in heart and breathing rate. However, some patients had only minimal changes in breathing and others had minimal psychophysiological changes during the time they indicated that they had a panic attack. Panic attacks are not homogeneous and may be characterized by a variety of physiological and cognitive responses. This may indicate that biological mechanisms of panic include abnormality in many functionally connected areas of the brain responsible for complex psychophysiological reactions to multiple threatening situations.

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.

The subjective response to a single-breath, 35% carbon dioxide challenge test shows promise as a tool for the study of panic disorder and may comprise a trait marker for that disorder. Little has been done to measure the reliability of test results, however. Subjects took a single breath at 35% CO2 and completed a self-rating of anxiety symptoms immediately thereafter. This procedure was repeated after a mean interval of 29 days. One group, considered at high risk for panic disorder, consisted of well, first-degree relatives of individuals treated for panic disorder. The control group included well subjects at high risk for affective disorder and subjects who had family histories negative for both affective disorder and panic disorder. On both testing occasions, subjects at high risk for panic disorder had symptom scores that were significantly higher than those of control subjects. Group differences in the portions who experienced a panic attack were dependent on the symptom threshold used to define an attack. A lower threshold was optimal with the second testing and a single, positive test result appeared to be more meaningful than a single negative result. The majority of individual symptom ratings were highly correlated across tests. Ratings for "smothering sensations," in particular, correlated highly across tests and consistently discriminated high-risk from control subjects. The sources of test result variability are unclear and warrant more investigation before the tests can be clinically useful. Research efforts should seek optimal thresholds to define positive test results within given data sets.

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.

Background: Respiratory symptoms are important in panic disorder for frequency and intensity. Patients with this disorder are often chronic hyperventilators, and inhalation of carbon dioxide is a strong panicogenic stimulus. We tested the hypothesis of whether respiratory parameters may be used as indicators of the course of panic disorder during its treatment with fluoxetine., Methods: Nine patients with panic disorders, previously shown to panic in response to intravenously administered lactate, and 10 control subjects underwent the Read rebreathing test by a 5-min inhalation of a 7% CO2/93% O2 mixture before and after 1 month of fluoxetine treatment., Results: At baseline, patients differed from controls for higher percent value of expiratory reserve volume/vital capacity ratio and ventilatory response. Eight of the 9 patients had panic in response to the CO2 challenge. After fluoxetine, respiratory parameters decreased significatively, and only 3 patients remained hypercarbic challenge responders., Conclusions: The carbon dioxide challenge may represent a useful tool to evaluate the individual respiratory set, which may be a marker of the vulnerability to panic attack. Assessment of respiratory parameters may represent a biological marker to measure the efficacy of antipanic treatment.

Objective: Patients with recurrent chest pain but no evidence of coronary artery disease often meet diagnostic criteria for panic disorder (PD). However, it can be argued that the phenomenological diagnosis of PD may not be valid in these normal coronary chest pain (NCCP) patients. The purpose of this study is to additionally validate the diagnosis of PD in chest pain patients by comparing PCO2 levels before and during myocardial stress scintigraphy in those with and without PD., Method: End-tidal PCO2 was measured before and during myocardial stress scintigraphy in 22 patients being evaluated for chest pain. Psychiatric diagnoses were assessed by structured interview., Results: Eleven of the 19 patients (58%) with negative scintigrams met DSM-III-R diagnostic criteria for current panic disorder. Prestress PCO2 levels were significantly lower in these patients. Eight of the nine NCCP patients with prestress PCO2 < 34 mm Hg had PD., Conclusions: The finding of stress-related hypocapnia associated with PD in NCCP patients provides additional support for the validity of the diagnosis of PD in this population. The potential value of PCO2 measurements in screening for PD in patients with chest pain merits additional study.