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.

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

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

Physiological changes during carbon dioxide inhalation in patients with panic disorder, major depression, and premenstrual dysphoric disorder: evidence for a central fear mechanism.

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.

Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder.

OBJECTIVE: The behavioral response to CO(2) inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of CO(2)-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO(2) inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO(2), administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each CO(2) inhalation. RESULTS: Panic disorder patients had a higher rate of CO(2)-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with CO(2)-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent CO(2) was a more robust panicogen than 5%, and response to 7% CO(2 )better distinguished panic disorder patients from normal subjects than response to 5% CO(2). CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO(2)-induced panic attacks, and depressed patients appear to be insensitive to CO(2) inhalation. The symptoms of CO(2)-induced panic attacks have a similar intensity regardless of the subject's diagnosis.

Efficacy of venlafaxine in mixed depression-anxiety states.

Patients with depression almost always suffer from comorbid anxiety or anxiety disorder. It is commonly stated that comorbid depression and anxiety has a worse prognosis, even with adequate therapy, than depression alone. An accumulation of data now make clear that the antidepressants venlafaxine and venlafaxine XR are effective in reducing anxiety in patients with depression. Several of the studies supporting this are reviewed here. Venlafaxine and venlafaxine XR have also been shown to be effective in treating anxiety disorders and venlafaxine XR is presently the only antidepressant approved by the FDA for the specific treatment of generalized anxiety disorder. The effectiveness of venlafaxine in treating anxiety associated with depression and anxiety disorders supports theories implicating abnormal noradrenergic activity as a component of pathological anxiety.

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

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

Efficacy of open-label nefazodone treatment in patients with panic disorder.

Fifteen patients with panic disorder participated in a 12-week treatment trial with open-label nefazodone. Nefazodone was well-tolerated with minimal side effects; none of the patients reported sexual dysfunction, and only one patient experienced weight gain. Although the response rate was lower than that found with most other antipanic medications, given its favorable side effect profile, nefazodone may be a good alternative for patients apprehensive about potential adverse drug reactions.

How study of respiratory physiology aided our understanding of abnormal brain function in panic disorder.

There is a substantial body of literature demonstrating that stimulation of respiration (hyperventilation) is a common event in panic disorder patients during panic attack episodes. Further, a number of abnormalities in respiration, such as enhanced CO2 sensitivity, have been detected in panic patients. This led some to posit that there is a fundamental abnormality in the physiological mechanisms that control breathing in panic disorder and that this abnormality is central to illness etiology. More recently, however, evidence has accumulated suggesting that respiratory physiology is normal in panic patients and that their tendency to hyperventilate and to react with panic to respiratory stimulants like CO2 represents the triggering of a hypersensitive fear network. The fear network anatomy is taken from preclinical studies that have identified the brain pathways that subserve the acquisition and maintenance of conditioned fear. Included are the amygdala and its brain stem projections, the hippocampus, and the medial prefrontal cortex. Although attempts to image this system in patients during panic attacks have been difficult, the theory that the fear network is operative and hyperactive in panic patients explains why both medication and psychosocial therapies are clearly effective. Studies of respiration in panic disorder are an excellent example of the way in which peripheral markers have guided researchers in developing a more complete picture of the neural events that occur in psychopathological states.

Plasma anti-serotonin and serotonin anti-idiotypic antibodies are elevated in panic disorder.

The psychoneuroimmunology of panic disorder is relatively unexplored. Alterations within brain stress systems that secondarily influence the immune system have been documented. A recent report indicated elevations of serotonin (5-HT) and ganglioside antibodies in patients with primary fibromyalgia, a condition with documented associations with panic disorder. In line with our interest in dysregulated 5-HT systems in panic disorder (PD), we wished to assess if antibodies directed at the 5-HT system were elevated in patients with PD in comparison to healthy volunteers. Sixty-three patients with panic disorder and 26 healthy volunteers were diagnosed by the SCID. Employing ELISA, we measured anti-5-HT and 5-HT anti-idiotypic antibodies (which are directed at 5-HT receptors). To include all subjects in one experiment, three different batches were run during the ELISA. Plasma serotonin anti-idiotypic antibodies: there was a significant group effect [patients > controls (p = .007)] and batch effect but no interaction. The mean effect size for the three batches was .76. Following Z-score transformation of each separate batch and then combining all scores, patients demonstrated significantly elevated levels of plasma serotonin anti-idiotypic antibodies. Neither sex nor age as covariates affected the significance of the results. There was a strong correlation between anti-serotonin antibody and serotonin anti-idiotypic antibody measures. Plasma anti-serotonin antibodies: there was a significant diagnosis effect [patients > controls (p = .037)]. Mean effect size for the three batches was .52. Upon Z-score transformation, there was a diagnosis effect with antibody elevations in patients. Covaried for sex and age, the result falls below significance to trend levels. The data raise the possibility that psychoimmune dysfunction, specifically related to the 5-HT system, may be present in PD. Potential interruption of 5-HT neurotransmission through autoimmune mechanisms may be of pathophysiologic significance in certain patients with panic disorder. It remains to be demonstrated if the peripheral autoimmunity is representative of CNS 5-HT neuronal alterations. Replication appears warranted.

Pretreatment patient factors predicting attrition from a multicenter randomized controlled treatment study for panic disorder.

This study examined pretreatment factors associated with attrition from a clinical trial for panic disorder. The study group consisted of 162 patients who began 11-visit treatments. Six domains (demography, panic disorder severity, psychiatric comorbidity, illness/treatment attributions, coping styles, and personality styles) with 52 variables were used to predict attrition. One hundred twenty-two patients completed and 40 dropped out from treatment. Final multivariate regression analyses showed that the following two variables were independently associated with attrition: lower household income and negative treatment attitudes; attributing the panic disorder to life stressors and greater age were independently associated with attrition at the trend level. Preliminary analyses suggested, in addition, associations between attrition and lower education, shorter length of prior treatment, higher anxiety sensitivity, lower agoraphobic avoidance, and a coping style of seeking social support that were not confirmed by best predictor analysis. Psychiatric comorbidity and personality styles were unrelated to attrition. The implications of these findings for future research and clinical practice are discussed.

Low-dose venlafaxine treatment in panic disorder.

Venlafaxine, a structurally novel antidepressant that combines mechanisms of action of both the cyclic antidepressants and SSRIs, may be effective in the treatment of panic disorder. Thirteen patients with DSM-IV panic disorder with or without agoraphobia participated in an open-label, fixed-flexible dose treatment study with venlafaxine. All patients who completed the 10-week trial exhibited statistically significant decreases in scores on anxiety symptoms as well as complete cessation of panic attacks at an effective mean daily dose of 47 mg per day. Venlafaxine was well tolerated in all completers. Venlafaxine may be an effective antipanic agent, even at lower than typical antidepressant dosages.

Plasma cortisol concentrations preceding lactate-induced panic. Psychological, biochemical, and physiological correlates.

BACKGROUND: We evaluated the role of plasma cortisol levels in determining sodium lactate-induced panic by reporting psychological, physiological, and biochemical data collected from an extended sample of 214 subjects during the "placebo" infusion (isotonic saline solution) immediately preceding the lactate infusion procedure. METHODS: One hundred seventy patients with panic disorder, 101 (59%) of whom were assessed to have panicked (P group), and 69 (41%) who were assessed not to have panicked (NP group) with lactate infusion; and 44 normal healthy volunteer controls (1 of whom panicked with lactate infusion) were studied. RESULTS: Before the lactate infusion, the P group exhibited hypothalamic-pituitary-adrenal (HPA) axis activation (high plasma cortisol levels) and evidence of hyperventilation (low PCO2 levels) in comparison with NP and control groups. Self-reported fear, dyspnea, and diastolic blood pressure were highest in the P group, intermediate in the NP group, and lowest in the control group. Within the P group, baseline fear scores correlated inversely with PCO2 levels and positively with cortisol levels while PCO2 levels correlated negatively with cortisol levels. Significant predictors of lactate-induced panic were prelactate infusion fear and the interaction of high cortisol levels and low PCO2 levels. CONCLUSION: Combined data suggest that synchronized elevations of HPA axis activity, self-reported fear, and hyperventilation during the period before lactate infusion predisposes to lactate-induced panic.

Ventilatory physiology of children and adolescents with anxiety disorders.

BACKGROUND: Abnormalities in ventilatory physiology have been noted in adults with panic disorder. We tested the hypothesis that abnormalities in ventilatory physiology differentiate children and adolescents with anxiety disorders from psychiatrically healthy children. METHODS: Ventilatory physiology was monitored with a canopy apparatus during room-air breathing and 15 minutes of carbon dioxide exposure in 33 children and adolescents comprising 18 probands with an anxiety disorder and 15 psychiatrically healthy children. RESULTS: During room-air breathing, probands had significantly larger minute ventilation, larger tidal volumes, and more variable breathing patterns than healthy comparisons, but the groups did not differ in end-tidal carbon dioxide or respiratory rate. During carbon dioxide challenge, probands exhibited larger minute ventilation and respiratory rate responses relative to comparisons. CONCLUSION: These findings on the association between ventilatory physiology and anxiety disorders in children and adolescents are consistent with results from studies of adults with panic disorder.

Hemodynamic response to respiratory challenges in panic disorder.

This study compares the hemodynamic response to panic disorder subjects with that of normal controls during respiratory challenges. Panic patients meeting DSM-IIIR criteria for panic disorder and normal controls were challenged with room air hyperventilation, 5% CO2 breathing, and 7% CO2 breathing. Measurements of pulse and blood pressure were taken at resting baseline and before and at the end of each respiratory challenge. Panic attack to each challenge was determined by using raters blinded to subject diagnosis and each subject's self-rating of panic. Significantly larger systolic and diastolic blood pressure increases were found in patients who panicked with room air hyperventilation than nonpanicking patients or normal controls. No significant blood pressure differences were found with 7% or 5% CO2 challenges, but higher pulse rates were found in the patient group. It may be possible that panic with room air hyperventilation causes a significant increase in systolic and diastolic blood pressure, or that a subgroup of panic disorder patients has a hyperactive vascular response to hypocapnia. These patients panic with room air hyperventilation and develop greater vasoconstriction and/or increased blood pressure response.

Pretreatment attrition in a comparative treatment outcome study on panic disorder.

OBJECTIVE: Whereas the fact of attrition during the course of treatment is well documented, little is known about the factors that affect sample selection before the beginning of a study ("pretreatment attrition"). The present study reports on the degree and sources of pretreatment attrition at two sites of a multicenter study on panic disorder that compared treatment outcomes for imipramine and cognitive behavior therapy. METHOD: Data were collected at two clinical research sites, one with a pharmacological treatment orientation (N = 420) and one with a psychosocial treatment orientation (N = 208). RESULTS: The main source of pretreatment attrition was participant refusal. At both research sites, eligible patients most often refused participation because they were either unwilling to start treatment with imipramine (30.6% and 47.4%, respectively) or discontinue their current medication (22.6% and 35.1%, respectively). CONCLUSIONS: Results from comparative treatment outcome studies are limited not only to people who meet the study criteria but also to those who are willing to begin a medication treatment and discontinue their current medication.

Effect of antipanic treatment on response to carbon dioxide.

BACKGROUND: Disordered breathing among patients with panic disorder, including hyperventilation during attacks and increased anxiogenic response to carbon dioxide (CO2) inhalation, is well established. We wished to assess whether there is a change in the physiological response to CO2 after patients have undergone antipanic therapy with either tricyclic antidepressants or cognitive behavioral therapy (CBT). METHODS: Twenty-nine patients with panic disorder underwent baseline CO2 sensitivity testing using the traditional Read rebreathing method and then received either antidepressant treatment (n = 21) or CBT (n = 8). After completing treatment, CO2 testing was repeated. A comparison sample of 14 normal volunteers also had two CO2 sensitivity tests, separated by an average of 21.6 (SD = 8.8) weeks. RESULTS: Using a liberal standard, in which all CO2 sensitivity tests whose correlations between minute ventilation and end-tidal CO2 were at least .75 were used, patients, but not controls, demonstrated a significant reduction in CO2 sensitivity between the first and second test. Using a more conservative .90 correlation standard reduced the sample size available and resulted in trend reduction in patients but no significant change in controls. There was a suggestion that the change was most pronounced in treatment responders, although the number of patient nonresponders is extremely small in this sample. CONCLUSIONS: These data indicate that treatment reduces CO2 sensitivity in patients with panic disorder. We speculate that manipulation of the serotonergic and noradrenergic neurotransmission systems, both known to play a role in the control of respiration, may have a specific effect in reducing respiratory hyperactivity in panic disorder.

Clomipramine treatment of panic disorder: pros and cons.

BACKGROUND: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance. METHOD: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day. RESULTS: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment. CONCLUSION: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.

Respiratory psychophysiology of panic disorder: three respiratory challenges in 98 subjects.

OBJECTIVE: Respiratory abnormalities may play a central role in the pathophysiology of panic disorder. The current study was undertaken to examine the respiratory response in the largest series of subjects to date during three respiratory challenges that used improved methodology. METHOD: Fifty-nine patients with DSM-III-R panic disorder and 39 normal volunteers were challenged with 5% and 7% CO2 inhalation and room air hyperventilation separated by room air breathing with continuous spirometry. RESULTS: Patients with panic disorder were more sensitive to the anxiogenic effects of CO2 than were normal subjects, and CO2 was a more potent stimulus to panic than hyperventilation. Patients increased their respiratory rate more quickly during CO2 inhalation than did comparison subjects, and this increase preceded the panic attacks. Patients who panicked in response to 5% CO2 demonstrated continued rise in end-tidal CO2, while the end-tidal CO2 of the comparison groups stabilized. Low end-tidal CO2 and high variance in minute ventilation at baseline predicted panic attacks during CO2 inhalation. Following CO2 or hyperventilation challenges, respiratory rate dropped sharply, while tidal volume remained elevated longer in patients than in comparison subjects. CONCLUSIONS: The findings confirm the greater behavioral and physiological sensitivity of patients with panic disorder to CO2 inhalation and identify a series of respiratory abnormalities. Panic attacks in panic disorder may be explained by inefficient compensatory mechanisms, primarily of respiratory rate.

Multicenter collaborative panic disorder severity scale.

OBJECTIVE: To address the lack of a simple and standardized instrument to assess overall panic disorder severity, the authors developed a scale for the measurement of panic disorder severity. METHOD: Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder (with no or mild agoraphobia) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder. In addition, 89 of these patients were reevaluated with the same scale after short-term treatment. A subset of 24 patients underwent two independent assessments to establish interrater reliability. Internal consistency, convergent and discriminant validity, and sensitivity to change were also determined. RESULTS: The Panic Disorder Severity Scale was associated with excellent interrater reliability, moderate internal consistency, and favorable levels of validity and sensitivity to change. Individual items showed good convergent and discriminant validity. Analysis suggested a two-factor model fit the data best. CONCLUSIONS: The Panic Disorder Severity Scale is a simple, efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder. However, further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed.