A three-year follow-up study of patients with the respiratory subtype of panic disorder after treatment with clonazepam

The demographic, clinical and therapeutic features of the respiratory subtype of panic disorder (PD) versus the non-respiratory subtype were studied in a prospective design. Sixty-seven PD outpatients (DSM-IV), who had previously been categorized into respiratory (n=35) and non-respiratory (n=32) subgroups, were openly treated with clonazepam for a 3-year period. The principal measure of efficacy was the number of panic attacks, obtained from the Sheehan Panic and Anticipatory Anxiety Scale. In the first 8 weeks of treatment (acute phase), the respiratory subtype group had a significantly faster response to clonazepam. During the follow-up (weeks 12-156), the two subgroups did not differ significantly in the number of panic attacks experienced from baseline to end point. Patients in the respiratory subtype were characterized by a later onset of disorder and a family history of PD. Patients in the non-respiratory subgroup had a significantly higher number of past depressive episodes than those in the respiratory subgroup. The respiratory subgroup had a faster response after 8 weeks of treatment and an equivalent response in the 3-year follow-up period. Clonazepam had a sustained therapeutic effect over the entire treatment period.     

Clinical Characteristics of the Respiratory Subtype in Panic Disorder Patients

Objective

Panic disorder has been suggested to be divided into the respiratory and non-respiratory subtypes in terms of its clinical presentations. The present study aimed to investigate whether there are any differences in treatment response and clinical characteristics between the respiratory and non-respiratory subtypes of panic disorder patients.

Methods

Among the 48 patients those who completed the study, 25 panic disorder patients were classified as the respiratory subtype, whereas 23 panic disorder patients were classified as the non-respiratory subtype. All patients were treated with escitalopram or paroxetine for 12 weeks. We measured clinical and psychological characteristics before and after pharmacotherapy using the Panic Disorder Severity Scale (PDSS), Albany Panic and Phobic Questionnaire (APPQ), Anxiety Sensitivity Index-Revised (ASI-R), State-Trait Anxiety Inventory (STAI-T, STAI-S), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D).

Results

The prevalence of the agoraphobia was significantly higher in the respiratory group than the non-respiratory group although there were no differences in gender and medication between the two groups. The respiratory group showed higher scores on the fear of respiratory symptoms of the ASI-R. In addition, after pharmacotherapy, the respiratory group showed more improvement in panic symptoms than the non-respiratory group.

Conclusion

Panic disorder patients with the respiratory subtype showed more severe clinical presentations, but a greater treatment response to SSRIs than those with non-respiratory subtype. Thus, classification of panic disorder patients as respiratory and non-respiratory subtypes may be useful to predict clinical course and treatment response to SSRIs.     

Clinical features of respiratory and nocturnal panic disorder subtypes

Our aim is to compare the panic disorder (PD) respiratory subtype and the nocturnal panic subtype. A group of 193 PD patients (DSM-IV) was examined in the Laboratory of Panic and Respiration in the Institute of Psychiatry of the Federal University of Rio de Janeiro. The diagnoses were made using the SCID-I for DSM-IV. The subtypes were the respiratory (with 4 out of 5 prominent respiratory symptoms during the panic attacks [PA]) vs. non-respiratory, likewise PD with nocturnal (during sleep) PAs vs. PD with only diurnal PAs. The respiratory subtype accounted for 56.5% (n=109) of our sample; the non-respiratory subtype, 43.5% (n=84); the nocturnal subtype, 49.2% (n=95); and the non-nocturnal subtype, 50.8% (n=98). Despite a rich literature concerning correlations between the respiratory system and nocturnal panic attacks, our data do not support these findings, as the comparison of proportions in the respiratory and nocturnal groups did not differ. The non-nocturnal subtype was significantly associated with agoraphobia, and the respiratory subtype was not associated with these variables.     

Anxiety sensitivity as a predictor of panic attacks

Anxiety sensitivity (AS) is the fear of physical symptoms of anxiety and related sensations believed to have harmful consequences. AS may play a central role in the nature and etiology of panic disorder (PD) and the genesis of panic attacks. We collected Anxiety Sensitivity Index (ASI) scores from PD patients and controls to determine if AS accurately predicts panic. ASIs were completed prior to panic induction using the modified Read rebreathing test in both hypoxic and hyperoxic conditions. Total scores first-order factors, and individual item ASI scores were correlated with panic presence (Spearman correlation) for each of the hypoxic and hyperoxic rebreathing tests for both study populations. Control subjects' data correlated significantly for items 4, 8, and 11 of the ASI for the hyperoxic (n=9; r_S=0.63, 0.70, and 0.63, respectively) and items 4 and 8 for the hypoxic rebreathing tests (n=9; r_S=0.63 and 0.70, respectively). Panic patients' data correlated significantly for item 1 of the ASI for hyperoxic tests (n=8; r_S=0.76) and item 5 for the hypoxic tests (n=8; r_S=0.95). Total ASI scores or first-order factors (physical, social concerns, and mental incapacitation) scores of either study group did not correlate significantly with panic presence. AS may not be a reliable predictor of panicogenic responses to CO₂-induced panic in either PD or normal control populations. AS may not be an ultimate causal element in eliciting panic attacks.     

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.     

Psychoeducation in panic disorder patients: effect of a self-information booklet in a randomized,masked-rater study

The aim of our study was to evaluate the effectiveness of a self-information booklet (SIB) in decreasing anxiety and panic attacks in Panic Disorder (PD) patients. Eighty-four patients attending an outpatient clinic due to panic disorder were randomly chosen to receive paroxetine with/without a friendly-designed brochure. Follow-up was done by a masked rater after 1, 3,and 12 weeks in order to evaluate whether the co-administration of paroxetine and the brochure (Group A) had a beneficial effect over the administration of paroxetine alone (Group B). After 3 weeks of therapy, Group A patients had significantly greater improvement and lower scores on the Hamilton Anxiety Scale, the Panic Self Questionnaire, and the Visual Analog Scale. After 12 weeks, the differential improvement was not statistically significant and both groups had improved as compared to baseline. The administration of a psychoeducational brochure (SIB) to PD patients at the initiation of therapy had beneficial effects during the first weeks of treatment. Although this effect fades away, the role of the SIB is overstressed in its ability to increase well being and compliance, and reduce anxiety and panic attacks.     

35% Carbon dioxide and breath-holding challenge tests in panic disorder: a comparison with spontaneous panic attacks

Respiration and its control mechanisms may represent an important system involved in abnormal anxiety. Our aim was to compare the demographic and clinical features of patients with panic disorder (PD) with agoraphobia (DSM-IV) who had a panic attack after both the 35% carbon dioxide (CO(2)) test and the breath-holding test (CPA group), and compare them with PD patients who did not have a panic attack after both tests (NPA group). We examined 76 patients with PD who were administered a 35% CO(2)test and a breath-holding test within a 1-week interval. Anxiety scales were applied before and after each test. A panic attack was induced in 50 (65.8%) patients during the CO(2)test (chi(2) = 28.44, df = 1, P<.001) and in 40 (52.6%) patients during the breath-holding test (chi(2) = 15.35, df = 1, P = .036). All patients who had a panic attack during the breath-holding test also had a panic attack during the CO(2)test (n = 40; CPA group). Twenty-six (34.2%) patients with PD did not have a panic attack after both respiratory tests (NPA group). The CPA group had more (chi(2) = 21.67, df = 1, P = .011) respiratory PD subtype. In the CPA group, the disorder started earlier (Mann-Whitney, P<.001), had a higher familial prevalence of PD (chi(2) = 18.34, df = 1, P = .028), and had more previous depressive episodes (chi(2) = 23.59, df = 1, P<.001). Our data suggest that there is an association between respiratory PD subtype and the response to respiratory challenge tests: CO(2)and breath-holding. The CPA may be confirmed as a subgroup of respiratory PD subtype.     

Depersonalization in panic disorder: a clinical study

Panic disorder (PD) has been hypothesized to be a heterogeneous entity, with distinct clinical subgroups. The presence of depersonalization during panic attacks may distinguish a specific subgroup of PD. We sought to analyze the differential features of a subgroup of PD patients with depersonalization. A total of 274 patients with PD were assessed and divided into 2 groups according to the presence or absence of depersonalization. The Structured Clinical Interview for DSM-III-R (SCID-UP-R) was used to assess PD and comorbid disorders. The clinical scales administered included the Hamilton Anxiety and Depression Rating Scale (HARS and HDRS), the Marks and Mathews Fears and Phobia Scale, Panic-Associated Symptom Scale (PASS), and a panic attack symptoms inventory. A total of 66 patients (24.1%) exhibited depersonalization during the attacks. Patients with depersonalization appeared to be younger and had an earlier age at onset. PD was more severe in the depersonalization group (greater number of attacks, worse level of functioning, and higher scores on most self-rating scales). Also, depersonalization patients showed more comorbidity with specific phobia. Our results support the view that PD with depersonalization may be considered a distinct and more severe subcategory of PD.     

The use of the Panic and Agoraphobia Scale (P & A) in a controlled clinical trial

BACKGROUND: A new 13-item scale has been developed for measuring severity of illness in patients with panic disorder and agoraphobia, the Panic and Agoraphobia Scale (P & A). The scale has five subscales covering the main factors that reduce quality of life in panic disorder patients (panic attacks, avoidance, anticipatory anxiety, disability and worries about health). The application of this scale in a double-blind placebo-controlled panic disorder trial is described. At the same time, the aim of the study was to compare the therapeutic effects of aerobic exercise with a treatment of well-documented efficacy. METHODS: Patients with Panic disorder (DSM-IV) were randomly assigned to three treatment modalities: running (n=45), clomipramine (n=15) or placebo (n=15). Treatment efficacy was measured with the Panic and Agoraphobia Scale (P & A) and other rating scales. RESULTS: According to the P & A and other scales, both exercise and clomipramine led to a significant decrease of symptoms in comparison to placebo treatment. Clomipramine was significantly more effective and improved anxiety symptoms significantly earlier than exercise. The evaluation of the P & A subscales revealed that exercise exerted its effect mainly reducing anticipatory anxiew and panic-related disability. CONCLUSIONS: The new Panic and Agoraphobia Scale was shown to be sensitive to differences between different panic treatments. Analysis of the scales five subscores may help to understand mechanisms of action of panic disorder treatments.     

Panic disorder and subthreshold panic in the light of comorbidity: a follow-up study

Especially in the presence of agoraphobia and comorbid conditions, panic disorder causes significant impairment in life quality. Although there are several studies about epidemiology and clinical features, subthreshold symptoms and courses of comorbidity have not been studied sufficiently in panic disorder. The current study assessed the courses of panic disorder and subthreshold panic symptoms in consideration of the major and subthreshold comorbid conditions. Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-diagnosed panic disorder were assessed using the panic disorder follow-up questionnaire, Panic and Agoraphobia Scale, Hamilton Depression Rating Scale, and State-Trait Anxiety Inventory. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders was used to determine comorbidity, and all participants were received to 1-year follow-up. Comorbidity assessment showed that the threshold comorbidity decreased, while the subthreshold comorbidity increased at 1-year follow-up. Panic disorder symptom severity was decreased, but subthreshold panic symptoms continued to be present within the course of the illness. Presence of agoraphobia and duration of disease were significantly related with higher Panic and Agoraphobia Scale scores in the second assessment, and these relationships were independent from the treatment process. Even if the comorbidity and the severity of panic decrease with treatment, subthreshold panic and comorbid symptoms may still resist in panic disorder.     

Psychological characteristics of early remitters in patients with panic disorder

We aimed to examine whether anxiety sensitivity and agoraphobic fear could affect the time taken to remission after 24 weeks of open-label escitalopram treatment of patients with panic disorder (PD). We recruited 158 patients, and 101 patients completed the study. Clinical severity and psychological characteristics were assessed at baseline and 4, 12, and 24 weeks after the treatment, using the Clinical Global Impression-Severity (CGI-S), the Hamilton Rating Scales for Anxiety and Depression, the Anxiety Sensitivity Index-Revised (ASI-R), the Albany Panic and Phobia Questionnaire (APPQ), and the Panic Disorder Severity Scale (PDSS). Remission was defined as the absence of full panic attacks and PDSS scores of 7 or less. Completing patients were stratified according to the time taken to remit: early (n=20) and late (n=58) remission and non-remission groups (n=23). There were no significant differences among the three groups at baseline on the CGI-S and the PDSS mean scores. However, early remitters had significantly lower scores than late remitters and non-remitters on the ASI-R and APPQ. In conclusion, anxiety sensitivity and agoraphobic fear can affect the time to remission after pharmacotherapy, and clinicians should consider the psychological characteristics of PD patients in order to achieve an optimal response to pharmacotherapy.     

Respiratory variability in panic disorder.

Disordered breathing may play an important role in the pathophysiology of panic disorder. Several studies have now indicated that panic disorder patients have greater respiratory variability than normal controls. In this study, we examine baseline respiratory measures in four diagnostic groups to determine whether greater respiratory variability is specific to panic disorder and whether effective anti-panic treatment alters respiratory variability. Patients with panic disorder, major depression, or premenstrual dysphoric disorder, and normal control subjects underwent two respiratory exposures (5% and 7% CO(2) inhalation), while in a canopy system. Panic disorder patients returned after 12 weeks of either anti-panic medication or cognitive behavioral therapy, and were retested. Normal control subjects were also retested after a period of 12 weeks. Panic disorder patients had significantly greater respiratory variability at baseline than normal control subjects and patients with major depression. The premenstrual dysphoric patients also had greater variability than the normal control group. Panic disorder patients who panicked to 7% CO(2) inhalation had significantly greater baseline variability than panic disorder patients who did not panic. Anti-panic treatment did not significantly alter baseline respiratory variability. Our data suggest that increased respiratory variability may be an important trait feature for some panic disorder patients and may make them more vulnerable to CO(2)-induced panic.     

Response to 5% carbon dioxide in children and adolescents: relationship to panic disorder in parents and anxiety disorders in subjects

BACKGROUND: Carbon dioxide (CO(2)) sensitivity is postulated to be a familial risk marker of panic disorder (PD). Exaggerated responses to CO(2) inhalation have been reported in adults with PD and their unaffected adult relatives, as well as in clinic-referred children with anxiety disorders. OBJECTIVE: To test in a family-based design whether CO(2) hypersensitivity is a familial risk marker for PD and associated with current anxiety disorders in children and adolescents. SETTING AND PARTICIPANTS: One hundred forty-two offspring (aged 9-19 years) of parents with PD, major depressive disorder, or no disorder. Forty-five (32%) had a current anxiety disorder, excluding specific phobia. DESIGN AND MAIN OUTCOME MEASURES: Parents and offspring received diagnostic assessments. Offspring underwent 5% CO(2) inhalation at home. Panic symptoms and panic attacks were rated with the Acute Panic Inventory at baseline, while anticipating CO(2) delivery ("threat"), and during CO(2) inhalation. Respiratory rate and volume were measured with spirometry. RESULTS: No group differences were found in Acute Panic Inventory ratings at baseline or in respiratory measures during threat. Risk for PD was not associated with CO(2) sensitivity (panic symptoms and respiratory physiologic response). During CO(2) inhalation, offspring with anxiety disorders, relative to offspring without anxiety disorders, experienced significantly more panic symptoms and panic attacks, as well as elevated respiratory rates. During threat, panic symptoms were significantly and independently associated with both parental PD and offspring anxiety disorders. CONCLUSIONS: No support was obtained for CO(2) hypersensitivity as a familial risk marker for PD in children and adolescents. Links between childhood anxiety disorders and CO(2) sensitivity were replicated. Familial risk for PD in children and adolescents may be associated with vulnerability to anticipatory anxiety.     

The association between serotonin-related gene polymorphisms and panic disorder

Dysfunction of the serotonergic system has been hypothesized to play an important role in panic disorder. We investigated the 5-HT2A receptor (5HTR2A) and tryptophan hydroxylase (TPH) genes for an association with panic disorder (PD). Patients with PD (n=107) and control subjects (n=161) were genotyped for 5HTR2A 1438A/G, 5HTR2A 102T/C, and TPH218 A/C. The severity of their symptoms was measured using the Spielberger State-Trait Anxiety Inventory (STAI), Panic Disorder Severity Scale (PDSS), Anxiety Sensitivity Index (ASI), Acute Panic Inventory (API), and Hamilton's Rating Scale for Depression (HAMD). There were no significant differences in the genotype distributions or allelic frequencies in the three serotonergic polymorphisms between PD patients and normal controls. However, we found a significant difference in symptom severity among the genotypes of both the 5HTR2A 1438A/G and 102T/C polymorphisms. Although there were no significant differences in the genotype and allele distributions, we found a significant association between panic symptom severity and the serotonin 2A receptor gene. This result suggests that 5HTR2A 1438A/G and 102T/C polymorphic regions can be associated with the phenotype or the pathogenesis of panic disorder.     

Physiological and behavioral effects of naloxone and lactate in normal volunteers with relevance to the pathophysiology of panic disorder

This study investigates whether naloxone, an opioid receptor antagonist, could render normal controls, normally nonresponsive to panic inducing stimuli, sensitive to the physiological and behavioral effects of sodium lactate, a robust panicogen in panic disorder patients. Twelve normal controls received intravenous naloxone followed by sodium lactate. Four of these subjects underwent a separate infusion with naloxone followed by saline. Respiratory physiological symptoms were measured throughout. Clinical symptoms, assessed by the Acute Panic Inventory (API), an Anxiety Scale, and the Borg Breathlessness Scale, were recorded. Eight of the twelve subjects experienced strong physiological reactivity to naloxone-lactate manifested by significantly increased tidal volume. Concomitant increases in the API and Borg scales were demonstrated; however, fear or anxiety was not affected. The four subjects retested with naloxone followed by saline did not experience significant increases on any measure. These results provide preliminary evidence that endogenous opioid system function may be a key modulator of responsivity to sodium lactate. Dysregulation of the opioid system may potentially underlie critical aspects of panic disorder neurobiology, including respiratory abnormalities and suffocation sensitivity.     

Panic disorder respiratory subtype: a comparison between responses to hyperventilation and CO2 challenge tests

In this study 117 panic disorder patients were divided into a respiratory subtype group and a non-respiratory subtype group. The respiratory subtype patients were observed to be more sensitive to the 35% CO(2) inhalation challenge test and the hyperventilation test than the non-respiratory subtype patients.     

Comparison between hyperventilation and breath-holding in panic disorder: patients responsive and non-responsive to both tests

Our aim was to compare the demographic and psychopathological features of panic disorder (PD) patients who underwent hyperventilation and breath-holding challenge tests, and to describe the features of patients who had a panic attack after both tests versus those patients who did not experience panic after either test. Eighty-five PD patients were induced to hyperventilate (30 breaths/min) for 4 min, and a week later to hold their breath for as long as possible four times with a 2-min interval in between. Anxiety scales were applied before and after the tests. Patients who responded with a panic attack to both tests (BPA, n = 25) were compared with patients who experienced spontaneous panic attacks but did not panic in response to the two tests (NPA, n = 16). The BPA group had a significantly higher presence of respiratory symptoms during a panic attack. The criteria for the respiratory PD subtype were fulfilled in 18 (72.0%) BPA patients and in 6 (37.5%) NPA patients. The BPA patients had a later onset of panic disorder and a higher familial prevalence of PD. Our data suggest that there is a distinction between PD patients who were sensitive to both hyperventilation and breath-holding tests and PD patients who were not affected by the challenge tests. The panic attack may be a final common pathway for different types of stimuli, and respiratory tests may characterize different PD subgroups.     

Doxapram-induced panic attacks and cortisol elevation

Numerous agents with differing biological properties and central nervous system (CNS) effects can induce panic attacks in predisposed individuals. A potential explanation of this finding is that panic disorder patients are more likely to panic than normal control subjects when given a panicogen due to an excessive fear response to somatic arousal. We test this hypothesis by using doxapram, a panicogen with minimal CNS effects, to induce panic in patients and control subjects. Doxapram was given to six subjects with panic disorder with or without agoraphobia and four healthy volunteers. Measures comprised the Acute Panic Inventory, the Borg Exertion scale, the 10-point Anxiety Scale, the 10-point Apprehension Scale, cortisol, prolactin, and MHPG, all obtained at baseline and multiple time points after the doxapram infusion. All panic disorder patients panicked with doxapram, whereas no control subjects had a panic attack. Panic patients had similar levels of breathlessness with doxapram compared with control subjects. Although panic patients had higher levels of anxiety and apprehension, these did not change significantly with doxapram compared with control levels. Doxapram led to similar increases in cortisol and prolactin in both groups, and MHPG was consistently elevated in panic patients, but unaffected by doxapram. These results show that doxapram is a useful panicogen in the study of panic disorder. Since the panic patients and control subjects had similar levels of physiological and psychological arousal, but the panic patients were more likely to have a panic attack, this lends support to the concept of a sensitized fear network in panic disorder patients.     

Panic disorder and hyperventilation

Respiratory abnormalities are associated with anxiety, particularly with panic attacks. Symptoms such as shortness of breath, "empty-head" feeling, dizziness, paresthesias and tachypnea have been described in the psychiatric and respiratory physiology related to panic disorder. Panic disorder patients exhibit both behaviorally and physiologically abnormal responses to respiratory challenges tests. OBJECTIVE: We aim to observe the induction of panic attacks by hyperventilation in a group of panic disorder patients (DSM-IV). METHOD: 13 panic disorder patients and 11 normal volunteers were randomly selected. They were drug free for a week. They were induced to hyperventilate (30 breaths/min) for 3 minutes. Anxiety scales were taken before and after the test. RESULTS: 9 (69.2%) panic disorder patients and one (9.1%) of control subjects had a panic attack after hyperventilating (p < 0.05). CONCLUSION: The panic disorder group was more sensitive to hyperventilation than normal volunteers. The induction of panic attacks by voluntary hyperventilation may be a useful and simple test for validating the diagnosis in some specific panic disorder patients.     

Application of a new statistical approach to evaluate a clinical trial with panic disorder patients

In clinical trials in psychiatry, changes in severity are usually measured with ordinal level scales which are applied repeatedly during the trial, showing a constant decline in psychopathology scores as treatment leads to improvement. Previous non-parametric tests for repeated measures in factorial designs did not test the hypothesis that scale scores decrease constantly during the trial. A recently developed “rank test for ordered alternatives in a mixed model” was developed and applied to the data of a clinical trial in panic disorder. Thirty-seven outpatients with panic disorder and agoraphobia (PDA) were treated with imipramine (75–150 mg/day) in an 8-week open, prospective trial. Patients with intercurrent agoraphobia were instructed in practising self-exposure in their agoraphobic situations. The total score on the Panic and Agoraphobia Scale, the Hamilton Anxiety Scale (HAMA) and the Clinical Global Impression Scale (CGI) were used as the main efficacy measures. The new rank test showed significant treatment results in all scales applied. Treatment results were excellent, as was shown by a decrease in the average Panic and Agoraphobia Scale severity scores from 28.9 (range 14–45) to 13.3 (range 0–37; rank statistic T_n = 6.7; p < 0.0001). The largest effect size r_w of all clinician-rated scales was seen with the observer-rated version of the Panic and Agoraphobia Scale, although closely followed by the CGI and the HAMA. Among the self-rated scales, the Panic and Agoraphobia Scale also showed the largest effect size. All five subscores of the Panic and Agoraphobia Scale showed significant improvements. The highest treatment effect sizes were seen in the “panic attacks” subscore, followed by the “anticipatory anxiety” subscore. The new statistical test applied in this study, which has some advantages in comparison with previously applied tests, is suitable for psychiatric treatment evaluations since it can also be applied in the case of discrete repeated measurements. Received: 3 March 1998 / Accepted: 9 October 1998