Daniela Caldirola

Panic disorder: the role of the balance system

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

The 35% CO2 challenge test in patients with social phobia

Panic disorder (PD) and social phobia (SP) share many clinical, demographic and biological characteristics. To investigate the relationships between the two disorders, the responses to inhalation of a 35% carbon-dioxide (CO2) and 65% oxygen (O2) gas mixture were assessed. Sixteen patients with PD, 16 patients with SP, 13 patients with both SP and PD, seven patients with SP who experienced sporadic unexpected panic attacks and 16 healthy control subjects inhaled one vital capacity of 35% CO2 or compressed air. A double-blind, randomized, crossover design was used. PD patients and SP patients showed similar anxiogenic reactions to 35% CO2, both stronger than seen in control subjects. Patients with both disorders and SP patients with sporadic unexpected panic attacks reacted similarly to subjects with PD or SP alone. These results suggest that PD and SP share a common hypersensitivity to CO2 and thus might belong to the same spectrum of vulnerability.

Pharmacologic effect of imipramine, paroxetine, and sertraline on 35% carbon dioxide hypersensitivity in panic patients: a double-blind, random, placebo-controlled study.

The effects of short treatment (7 days) with the tricyclic antidepressant imipramine and the two selective serotonin reuptake inhibitors paroxetine and sertraline on the reactivity to inhalation of 35% CO2/65% O2 were compared in 70 panic patients who had positive responses to 35% CO2 inhalations. A double-blind, random, placebo-controlled design was applied. Each patient was given the 35% CO2 challenge on days 0 (before starting the treatment), 3, and 7. In the placebo group, there were no significant changes in the reactivity to 35% CO2 in the three sessions whereas there were significant similar reductions of reactivity to 35% CO2 in all three drug-treated groups. These results confirm the good reproducibility of 35% CO2 reactivity and the negligible effects of placebo on reactivity to CO2 and suggest that short treatments with imipramine, paroxetine, and sertraline decrease reactivity to 35% CO2, possibly as an expression of their antipanic properties.

Hypersensitivity to inhalation of carbon dioxide and panic attacks

Thirteen healthy subjects with infrequent panic attacks and without agoraphobia who did not meet DSM-III-R criteria for panic disorder, 43 patients with panic disorder, and 43 healthy control subjects who never experienced panic attacks underwent one vital capacity inhalation of 35% CO2. Healthy subjects with infrequent panic attacks reacted similarly to patients with panic disorder and more strongly than healthy subjects who never experienced panic attacks. The results suggest that (a) subjects with sporadic unexpected panic attacks and patients with panic disorder belong to the same spectrum of vulnerability and (b) CO2 hypersensitivity might be a trait marker of panic attacks rather than of a clinical diagnosis of panic disorder.

Panic attacks: a twin study

The role of genetic factors in panic disorder (PD) and sporadic panic attacks (SPAs) was investigated. A total of 120 twins recruited from the general population were interviewed for the presence of anxiety disorders and SPAs. A significantly higher concordance among MZ than DZ twins was found for PD (73% vs. 0%) but not for SPAs (57% vs. 43%). These results confirm a significant role of genetic factors in PD but suggest that genetic factors might not be crucial for the development of SPAs.

Panic disorder: from respiration to the homeostatic brain

There is some experimental evidence to support the existence of a connection between panic and respiration. However, only recent studies investigating the complexity of respiratory physiology have revealed consistent irregularities in respiratory pattern, suggesting that these abnormalities might be a vulnerability factor to panic attacks. The source of the high irregularity observed, together with unpleasant respiratory sensations in patients with panic disorder (PD), is still unclear and different underlying mechanisms might be hypothesized. It could be the result of compensatory responses to abnormal respiratory inputs or an intrinsic deranged activity in the brainstem network shaping the respiratory rhythm. Moreover, since basic physiological functions in the organism are strictly interrelated, with reciprocal modulations and abnormalities in cardiac and balance system function having been described in PD, the respiratory findings might arise from perturbations of these other basic systems or a more general dysfunction of the homeostatic brain. Phylogenetically ancient brain circuits process physiological perceptions/sensations linked to homeostatic functions, such as respiration, and the parabrachial nucleus might filter and integrate interoceptive information from the basic homeostatic functions. These physiological processes take place continuously and subconsciously and only occasionally do they pervade the conscious awareness as ‘primal emotions’. Panic attacks could be the expression of primal emotion arising from an abnormal modulation of the respiratory/homeostatic functions.

Antipanic drug modulation of 35% CO2 hyperreactivity and short-term treatment outcome

Carbon dioxide (CO2) inhalation induces acute anxiety and panic attacks in patients with Panic Disorder (PD). Anti-panic drugs decrease CO2 reactivity after the first days of treatment; however, the clinical meaning of this finding has not yet been established. This study investigated the effects of treatment with tricyclic antidepressants and selective serotonin re-uptake inhibitors (SSRIs) on CO2 reactivity and compared the relationships between 35% CO2 hyperreactivity modulation and short-term clinical outcome. One hundred twenty-three patients with PD with or without agoraphobia who were hyperreactive to CO2 were randomly assigned to treatment groups with imipramine, clomipramine, paroxetine, sertraline, or fluvoxamine. A double-blind, randomized design was applied. Each patient received the 35% CO2 challenge on days 0, 7, and 30. The severity of clinical symptomatology was measured on days 0 and 30. Decreased hyperreactivity to 35% CO2 in all five treatment groups was already evident after the first week. The decrease in CO2 reactivity at the end of treatment was proportional to the degree of clinical improvement. Multiple regression analyses showed that the decrease in CO2 reactivity after the first week was a significant predictor for good clinical outcome after one month. The results of this study confirm evidence that psychoactive drugs effective in the treatment of PD decrease CO2 hyperreactivity. They also suggest that precocious modulation of CO2 reactivity might fairly reliably predict short-term clinical outcome in patients with “respiratory” PD.

Smoking and respiratory irregularity in panic disorder.

BACKGROUND The biological mechanisms underlying the link between smoking and panic attacks are unknown. Smoking might increase the risk of panic by impairing respiratory system function. METHODS We evaluated the effect of smoking on respiratory irregularity in patients with panic disorder (PD) and healthy comparison subjects and the role of the respiratory disorders in this effect. We applied the Approximate Entropy index (ApEn), a nonlinear measure of irregularity, to study breath-by-breath baseline respiratory patterns in our sample. RESULTS Both smoker and nonsmoker patients had more irregular respiratory patterns than healthy subjects. Smoker patients showed higher ApEn indices of baseline respiratory rate and tidal volume than nonsmoker patients (R = 5.4, df = 2,55, p < .01), whereas smoking in healthy subjects did not influence the regularity of respiratory patterns. Respiratory disorders did not account for the influence of smoking on respiratory irregularity. Smokers had more severe panic attacks than nonsmokers. CONCLUSIONS Smoking may impair vulnerable respiratory function and act as disruptive factor on intrinsic baseline respiratory instability in patients with PD, possibly influencing the onset or maintenance of the disorder.

The 35% CO2 hyperreactivity and clinical symptomatology in patients with panic disorder after 1 week of treatment with citalopram: an open study.

The effect of a short treatment (7 days) with citalopram on the reactivity to inhalations of 35% CO 2 and 65% oxygen and on clinical symptomatology was investigated in 15 patients with panic disorder who had a positive response to 35% CO 2 inhalation. An open study design was applied. On day 0, before starting drug treatment, and after 1 week of treatment, each patient underwent the 35% CO 2 challenge, and clinical symptomatology was evaluated with psychometric scales. The results showed a significant reduction of CO 2 reactivity and of scores on the anticipatory anxiety subscale of Panic Associated Symptoms Scale. These results confirm that the serotonergic system plays an important role in the modulation of CO 2 hyperreactivity and suggest an early anxiolytic effect of citalopram in patients who have panic disorder and are hyperreactive to CO 2 .

Baseline respiratory parameters in panic disorder: a meta-analysis.

BACKGROUND The presence of abnormalities in baseline respiratory function of subjects with panic disorder (PD) is expected according to PD respiratory theories. We aimed to meta-analyze results from studies comparing baseline respiratory and hematic parameters related to respiration between subjects with PD and controls. METHODS A literature research in bibliographic databases was performed. Fixed-effects models were applied for all parameters while random-effects models only when suitable (at least 10 independent studies). Several moderator analyses and publication bias diagnostics were performed. RESULTS We found significantly higher mean minute ventilation and lower et-pCO(2) in subjects with PD than controls. Moreover we also found evidences of reduced HCO(3)(-) and PO(4)(-) hematic concentrations, higher indexes of respiratory variability/irregularity and higher rate of sighs and apneas. Evidence of heterogeneity was partly explained by moderator analyses. No relevant publication bias was found. LIMITATIONS Several shortcomings affected the included studies, such as over-inclusive recruitment criteria, samples unbalanced for socio-demographic characteristics, lack of statistical details and small number of studies available for several parameters. DISCUSSION Our results support the idea of abnormalities in respiratory function of subjects with PD. Compared to controls, they showed baseline hyperventilation; the results from hematic parameters suggest that hyperventilation may be chronic and not simply caused by their high anxiety levels during respiratory assessment. Evidences of higher variability and irregularity in respiratory patterns of subjects with PD were also found. It is unclear to what extent the higher rate of sighs and apneas may explain the other baseline respiratory abnormalities found in PD.