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Onset of Spontaneous Panic Attacks: A Prospective Study of Risk Factors

From the University of Iowa Carver College of Medicine, Iowa City, Iowa (W.C., L.D.); Columbia University School of Medicine, New York, New York (A.F.); National Institute of Mental Health, Bethesda, Maryland (D.S.P.).

Address correspondence and reprint requests to William Coryell, MD, University of Iowa Carver College of Medicine, Department of Psychiatry, 2–205 MEB, Iowa City, IA 52242. E-mail: william-coryell{at}uiowa.edu.

	ABSTRACT

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Objective: Earlier analyses have shown that, among currently well individuals with no history of panic attacks, a family history of panic disorder is associated with a greater likelihood of panic symptoms after exposure to 35% CO₂ and of ventilatory-response abnormalities during inhalation of 5% CO₂. An association of those features with a subsequent onset of panic attacks would compose additional evidence that they are trait markers for panic disorder.

Methods: Subjects who were free of current Axis I disorders other than simple or social phobia and who had a first-degree relative with panic disorder (high risk) and subjects who had no first-degree relatives with panic disorder or major depressive disorder (low-risk) underwent two challenge procedures. The first measured anxiety responses to a single breath of 35% CO₂, and the second measured ventilatory responses to a 3-minute exposure to 5% CO₂. After a mean interval of 4 years, 66 high-risk (48 female; mean age = 23.0 years) and 24 low-risk subjects (15 female; mean age = 23.1 years) were questioned by telephone about the occurrence of any spontaneous panic attack in the interval.

Results: Sixteen (23.9%) of the high-risk and one (4.2%) of low-risk subjects had experienced at least one spontaneous panic attack; Cox regression analyses revealed a significant relationship between abnormal ventilatory responses to 5% CO₂ and the later onset of panic attacks. Subjective responses to 35% CO₂ were not predictive. Neuroticism scores were not associated with abnormal ventilatory responses to CO₂ but were also predictive of later panic attacks.

Conclusions: High neuroticism scores and abnormal ventilatory responses to 5% CO₂ appear to be additive trait markers for panic disorder.

Key Words: panic disorder • carbon dioxide • trait marker • follow-up • neuroticism

Abbreviations: VAS-A = visual analogue scale–anxiety; DSM-III-R = Diagnostic and Statistical Manual III–Revised; MV = minute volume; NEO-PI = NEO Personality Inventory; HR = hazard ratio.

	INTRODUCTION

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Particular features that characterize individuals who are at high risk for an illness help to identify genotypes for that illness. The association of provisional trait markers with subsequent clinical manifestations of the illness composes additional evidence that the features do, in fact, signify a genotype.

Numerous studies have established that unmedicated individuals with panic disorder are more likely than well controls (1–8) or subjects with other psychiatric illnesses (3,9–11) to experience a panic attack after a single breath of 35% CO₂. The consistency of this finding has sparked extensive interest in respiratory abnormalities in general, and in sensitivity to carbon dioxide inhalation in particular, as possibly fundamental to the pathophysiology of panic disorder.

The results of four studies support the likelihood that a panic response to high-dose (35%) CO₂ inhalation comprises a genotype for panic disorder (7,12–14). Each confined their sample to individuals with no personal history of panic attacks, and each showed that those who had a first-degree relative with panic disorder were significantly more likely to experience a panic attack after a single breath of 35% CO₂ than were individuals who lacked such a family history. Familial transmission of this response does not necessarily imply a genetic component. Evidence for such a component, though, derives from a twin study in which concordance for panic reaction to 35% CO₂ was significantly higher for monozygotic than for dizygotic twins (15).

Our group also considered whether subjects at high risk for panic disorder might differ from low-risk controls by ventilatory responses to low doses of CO₂. Unexpectedly, a response to 5% CO₂ exposure in which subjects decreased their minute volume (MV) over time distinguished high-risk from low-risk subjects (16) much more robustly than did their subjective response to 35% CO₂ (14). We considered this a "paradoxic" response because the normal change during inhalation of increased concentrations of CO₂ is an increase in MV and because we had predicted that high-risk individuals were to have a particularly large increase. We later determined that individuals with this paradoxic response were significantly more likely to have a particular lactate dehydrogenase exon-5 haplotype than were individuals without this response (17).

Because our high-risk studies targeted individuals in their late teens and early twenties, most subjects had not passed the midpoint of the typical risk period of 15 to 35 years for panic disorder onset (18). We therefore attempted to determine who of the original high-risk subjects had experienced spontaneous panic attacks during the mean of 4 years since they underwent baseline clinical assessment and CO₂ challenge procedures.

	METHODS

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Subjects
Earlier publications have described the recruitment procedures and inclusion criteria (13,14). Between 1997 and 2002, inclusive, we used advertisement to enroll individuals 18 to 35 years old who could describe a first-degree relative who had been treated for panic disorder. Probands were required to lack a personal history of panic attacks or of any current Axis I disorder other than simple or social phobia. We used the same methods and inclusion criteria to recruit a low-risk control group of individuals who lacked any first-degree relative with panic disorder or major depressive disorder.

Procedures
Interviews for all subjects included the Schedule for Affective Disorders and Schizophrenia–Lifetime Version, Modified for the Study of Anxiety Disorders (19) and the Family Informant Schedule and Criteria (20). Subjects also completed a battery of self ratings that included the NEO Personality Inventory (NEO-PI) (21).

Also as previously described (13,14)all subjects underwent a 35% CO₂ challenge procedure in which they took a vital-capacity breath of 35% CO₂. This was followed by a low-dose challenge procedure in which the subject breathed room air for 3 minutes and then 5% CO₂ for 3 minutes. At the beginning and end of each procedure, subjects completed a visual analog scale (VAS) anchored at either end with "no anxiety at all" or "the worst anxiety you can imagine." They also completed an anxiety symptom checklist consisting of 14 disaggregated symptoms of a panic attack as defined by the Diagnostic and Statistical Manual III–Revised (DSM-III-R). Each symptom was rated on a 4-point scale from "0" ("not present") to "3" ("severe"). A threshold of four symptoms rated at 2 or 3 defined a panic attack.

Raters who were blind to both the baseline risk grouping and the CO₂ challenge results attempted to locate subjects a mean (SD) of 4.0 (1.4) years later. In a telephone interview of less than 5 minutes, subjects were reminded of their earlier study participation and were asked to describe any major changes in their health status since then. They were then asked whether they had experienced any panic attacks in the interval and were provided with a brief description of a typical panic attack for reference. The study was approved by the University of Iowa IRB.

Analyses
The present analysis uses two of the four measures of subjective responses to 35% CO₂ inhalation described previously (14): the difference in the visual analogue scale–anxiety (VAS–A) score after air inhalation versus that after CO₂ inhalation and the number of panic attack symptoms endorsed at at least a level 2 intensity after CO₂ inhalation.

We previously identified two abnormalities in ventilatory response to 5% CO₂ that significantly distinguished high-risk from low-risk subjects (16). Both derived from plots of breath-to-breath MV against time. The abnormality that most robustly separated groups was a negative MV slope. The second discriminating measure was an abnormally positive MV slope value with a numeric cutoff determined by visual inspection.

Our earlier analyses showed that the neuroticism scale score from the NEO-PI was the most robust of the self-rating scales in separating high- and low-risk groups (14). The present analysis therefore tested whether this measure interacted with CO₂ challenge results in predicting panic attack onset. The formula (Z-score x 10) + 50 was used to derive T-scores. These set the overall group mean at 50 and show group distances from that mean in standard deviation units.

Univariate comparisons of continuous variables and of categorical variables used t test and ² statistics, respectively. Because the length of follow-up varied from 2 to 7 years, we used SSPS Cox regression analyses to incorporate time effects on the outcome variable of panic attack onset. The SPSS Cox regression generates an EXP (B), or hazard ratio (HR). This is a value by which the odds of the event change when the predictor variable increases by one unit. Sample sizes differed by CO₂ challenge procedure in that three subjects were missing a 35% CO₂ challenge results and another nine were missing 5% ventilatory response measures.

	RESULTS

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Efforts to locate and interview 95 high-risk subjects and 38 low-risk controls were successful in 66 (69.5%) and 24 (63.2%) cases, respectively. Those followed resembled those lost at follow-up demographically. Twenty-one (72.4%) of the high-risk and 9 (64.3%) of the controls lost to follow-up were female, and mean (SD) ages were 23.9 (4.0) and 23.9 (3.9), respectively, and they therefore closely resembled those followed demographically (Table 1). Those not followed were also as likely as those followed to have abnormal ventilatory responses to 5% CO₂ inhalation (either a negative MV slope or an abnormally causative one): 21 (34.4%) of the high-risk subjects not followed, and 11 (37.9%) of those followed had abnormal ventilatory responses at baseline. Among control subjects 1 (7.1%) of those not followed and 2 (10.0%) of those followed had had abnormal ventilatory responses.

Follow-up interviews occurred a mean (SD) of 4.0 (1.4) years after baseline assessment. The high-risk subjects resembled low-risk subjects by age and sex and proportions with histories of major depressive disorder or of any anxiety disorder (Table 1). The high-risk group had significantly higher neuroticism scores at baseline.

Nearly a quarter (16 of 66, or 24.2%) of the high-risk subjects but only one (4.2%) of the low-risk subjects developed at least one spontaneous panic attack during the follow-up interval (p = .035, exact test). Risk status approached significance as a predictor in a Cox regression model (Wald ² = 3.38, df = 1, p = .066, HR = 6.69).

Those who developed panic attacks also had higher baseline neuroticism T-scores (mean = 57.1, SD = 10.3) than did those who did not (mean = 48.4; SD = 9.5) (t = –3.3, df = 87, p = .001). Neuroticism scores were less predictive in a Cox regression model (Wald ² = 3.4, df = 1, p = .063, HR = 1.11), and a significant interaction existed between risk status and neuroticism score (Wald ² = 5.6, df = 1, p = .018, HR = 1.03).

Subjective responses to 35% CO₂ inhalation showed no relationship to subsequent panic attack onset. The seventeen who developed panic attacks during follow-up and the 70 who did not had mean (SD) increases of VAS-A ratings of 20.3 (18.1) and 25.3 (21.8), respectively. Eleven (64.7%) and 45 (64.3%), respectively, had experienced abbreviated panic attacks after this challenge.

Of 22 individuals with a negative MV slope during 5% CO₂ exposure, 6 (27.3%) developed panic attack onset compared with nine of the 58 (15.5%) with normal MV slopes. The single individual who manifested an abnormally high MV slope developed panic attacks during follow-up. A Cox regression analysis showed that an abnormal ventilatory response to 5% CO₂ inhalation (either a negative or an abnormally high MV slope) was significantly predictive of later spontaneous panic attacks (Wald ² = 5.6, df = 1, p = .018, HR = 3.44). Subjects with abnormal ventilatory responses had baseline neuroticism scores similar to those of subjects with normal responses; mean (SD) values were 48.2 (11.5) and 51.1 (9.7), respectively (t = 1.1, df = 78, p = .25). Thus, inclusion of neuroticism in the model did not reduce the significance of the relationship between ventilatory response and likelihood of panic attack onset.

To explore the importance of follow-up length to these findings, the sample was divided into those with the follow-up length less than the median of 4 years and those with follow-ups of 4 to 7 years. Cox regression analyses showed an abnormal MV-slope response to 5% CO₂ exposure to be predictive of later spontaneous panic attacks for the 46 with longer follow-ups (Wald ² = 4.7, df = 1, p = .03, HR = 3.74) but not for the 21 with shorter follow-ups (Wald ² = 0.083, df = 1, p = .773, HR = 1.33).

High-risk subjects who had had an abnormal ventilatory response to 5% CO₂ had neuroticism scores that were somewhat lower than those for high-risk subjects who had normal responses. Mean (SD) values were 15.3 (9.3) and 19.2 (7.6), respectively (t = 1.74, df = 57, p = .088). To explore the predictive potential of neuroticism as a categorical measure in combination with responses to 5% CO₂, we determined the mean (SD) neuroticism score for the high-risk and low-risk groups combined, 16.7 (7.96). We then designated high-risk subjects with scores of 25 or more (mean + SD) as having high neuroticism.

The risk for onset of spontaneous panic attacks rose progressively from a low for those with normal 5% challenge results and nonhigh neuroticism scores to a high for those with abnormal MV response and high neuroticism (Table 2). Separate ROC analyses for subjects with abnormal ventilatory responses and for those with normal ventilatory response revealed similar areas under the curve of 0.76 and 0.70, respectively.

	DISCUSSION

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In a cohort of young adult subjects who denied any history of panic attacks, three baseline variables characterized those who went on to experience at least one panic attack during a mean follow-up period of 4 years: a first-degree relative with panic disorder, a high neuroticism score, and an abnormal ventilatory response to 5% CO₂ exposure. Only the last of these was a significant predictor in regression analyses that took length of follow-up into account. Subjects with positive family histories, considered to be at high risk for panic disorder, had higher neuroticism scores and were more likely to have had abnormal ventilatory responses to 5% CO₂ inhalation. The mean T-score for this group resembled that of simple phobics in a community survey, 51.5, but was lower than that of individuals with panic disorder, 56.5 (22). The mean T-score for the low-risk group, 46.4, resembled that of the community respondents who had none of the five possible DSM-III-R anxiety disorders. There was, however, no apparent relationship between neuroticism score and the likelihood of an abnormal ventilatory response. These two measures were therefore additive as risk factors for future panic attacks.

Other investigators have characterized ventilatory responses to CO₂ in patients with panic disorder. Some have shown patients to have steeper MV slopes than well controls while breathing CO₂ (23–25) or to have greater increases in respiratory frequency (26). Pine et al. (27) recently reported ventilatory responses to 15 minutes of 5% CO₂ among well children with family histories of panic disorder and found no difference in comparison to well children without family histories. None of these investigators sought to identify subgroups with negative MV slopes early during 5% CO₂ exposure. As noted in our earlier report, subjects with a negative MV slope coexisted with subjects who had abnormally positive MV slopes (16). As a consequence, the mean ventilatory response value in high-risk subjects resembled that of the family-history-negative subjects. Only an examination of MV-slope distributions revealed striking differences between high- and low-risk cohorts.

Chief among the weaknesses of this study is a follow-up that did not extend through the typical age-of-onset risk period. Ventilatory responses to 5% CO₂ exposure were not predictive for those followed less than 4 years. This indicates that a greater interval between the baseline and follow-up assessments may have revealed a more robust predictive relationship.

The accuracy with which panic attack onsets were ascertained was limited by a single follow-up interview that required the recall of symptoms up to 7 years in the past. The finding that the predicted relationship between baseline ventilatory response and later panic attack onsets emerged with longer rather than shorter follow-up intervals suggests that recall was sufficient despite the time elapsed.

The failure of subjective responses to 35% CO₂ inhalation to predict panic attack onset is not surprising, given the weak relationship between this response and risk status noted previously by our group (14). The results are similar to those of another study of a high-risk sample. Among 62 well individuals with anxiety sensitivity scores above the mean for a nonclinical population, 6 (9.7%) developed spontaneous panic attacks in a 1-year follow-up. These individuals were no more likely than those free of panic attacks to have experienced a panic attack with a baseline 35% CO₂ challenge (28). The fact that the proportion of well controls with panic attack responses to 35% CO₂ have ranged from 0% (14) to 24% (7) suggests that subtle differences in challenge procedures may have large effects on the specificity of the results. What these differences are, unfortunately, is not obvious.

Evidence that abnormal ventilatory responses to low-dose CO₂ exposure are genotypical for panic disorder now includes high specificity and moderate sensitivity for high-risk status as defined by family history, a significant association with a haplotype of lactate dehydrogenase (17), and a predictive relationship to the onset of panic attacks. All three lines of evidence, though, have been generated by one group, and all await replication. Such replication would clearly warrant further investigation into the physiological substrates of these abnormal ventilatory responses because these are more likely to reflect heritable and therefore fundamental causes of panic disorder than are abnormalities identified in clinical phenotypes.

	NOTES

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Received for publication October 12, 2005; revision received February 8, 2006.

DOI:10.1097/01.psy.0000232268.00327.b4

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