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Background: Anxiety symptoms are associated with a marked increase in sudden cardiac death, suggesting an abnormality in cardiac autonomic function. Our previous studies show a relationship between R amplitude variability and sympathetic function., Methods: We examined the effects of beta-adrenergic stimulation on R and T amplitude variability in panic disorder patients by infusing the beta-adrenergic agonist isoproterenol in 6 panic disorder patients and 11 normal subjects. The ECG signal was analyzed before the infusion and 5 min after the infusion was started. The outcome measures were the R and T detrended variance normalized for mean amplitudes (R(vm) and T(vm)) and the R(vi) and T(vi), measures which are normalized for the inter-beat interval variability in addition., Results: Patients with panic disorder had significantly more variability in R and T amplitude than normal controls and the R amplitude variability was increased further by beta-adrenergic stimulation with isoproterenol, which was more pronounced in the patients., Conclusions: The isoproterenol-associated increase in R amplitude variability occurred in controls in the absence of significant anxiety. However, the increase in R amplitude variability was greater in patients with panic disorder, suggesting a greater sensitivity to beta-adrenergic effects of isoproterenol or to isoproterenol-induced anxiety., ((c) 2007 S. Karger AG, Basel.)

Previous studies indicate that serotonin reuptake inhibitors do not appear to have serious cardiac side effects. However, the effects of these agents on respiratory measures have not been studied in detail. Several studies indicate that patients with anxiety exhibit irregular breathing patterns as measured by tidal volume and respiratory rate. In this study, we evaluated the effects of a serotonin reuptake inhibitor, paroxetine, on respiratory variability in patients with panic disorder (n = 13), using linear and nonlinear measures of regularity, approximate entropy (APEN) and a measure of chaos, the largest Lyapunov exponent (LLE), with pre- and posttreatment lung volume time series (256 s long sampled at 4 Hz). Our results show that paroxetine significantly decreases some of the linear measures of variability and supine APEN and standing LLE of lung volume series after successful treatment. The implications of these findings on respiratory and cardiovascular function have been discussed., (Copyright 2004 S. Karger AG, Basel)

Background: Respiratory irregularity has been previously reported in patients with panic disorder using time domain measures. However, the respiratory signal is not entirely linear and a few previous studies used approximate entropy (APEN), a measure of regularity of time series. We have been studying APEN and other nonlinear measures including a measure of chaos, the largest Lyapunov exponent (LLE) of heart rate time series, in some detail. In this study, we used these measures of respiration to compare normal controls (n = 18) and patients with panic disorder (n = 22) in addition to the traditional time domain measures of respiratory rate and tidal volume., Methods: Respiratory signal was obtained by the Respitrace system using a thoracic and an abdominal belt, which was digitized at 500 Hz. Later, the time series were constructed at 4 Hz, as the highest frequency in this signal is limited to 0.5 Hz. We used 256 s of data (1024 points) during supine and standing postures under normal breathing and controlled breathing at 12 breaths/min., Results: APEN was significantly higher in patients in standing posture during normal as well as controlled breathing (p = 0.002 and 0.02, respectively). LLE was also significantly higher in standing posture during normal breathing (p = 0.009). Similarly, the time domain measures of standard deviations and the coefficient of variation (COV) of tidal volume (TV) were significantly higher in the patient group (p = 0.02 and 0.004, respectively). The frequency of sighs was also higher in the patient group in standing posture (p = 0.02). In standing posture, LLE (p < 0.05) as well as APEN (p < 0.01) contributed significantly toward the separation of the two groups over and beyond the linear measure, i.e. the COV of TV., Conclusion: These findings support the previously described respiratory irregularity in patients with panic disorder and also illustrate the utility of nonlinear measures such as APEN and LLE as additional measures toward a better understanding of the abnormalities of respiratory physiology in similar patient populations as the correlation between LLE, APEN and some of the time domain measures only explained up to 50-60% of the variation., (Copyright 2002 S. Karger AG, Basel)

Recent studies on beat-to-beat QT interval variability (QTV) have shown that it can be used as a noninvasive measure of cardiac repolarization lability. It is also a predictor of sudden cardiac death and is higher in patients with anxiety and depression. This study examined the diurnal measures in QTV in 32 normal adults and 22 patients using 24-hour electrocardiogram records. We obtained 8 5-min segments of ECG sampled at 1,000 Hz from the 24-hour records. Our results show that QTV measures at nighttime are significantly higher in patients with panic disorder compared with controls. These findings demonstrate blunted diurnal changes in ventricular repolarization lability in patients resulting in a higher QT variability index during sleep. We speculate that these effects may relate to a relative increase in cardiac sympathetic activity in patients with panic disorder, and may contribute to the increased risk for cardiac mortality in patients with anxiety., (Copyright 2002 S. Karger AG, Basel)

Depression is associated with increased cardiovascular mortality in patients with preexisting cardiac illness. A decrease in cardiac vagal function as suggested by a decrease in heart rate variability (HRV) or heart period variability has been linked to sudden death in patients with cardiac disease as well as in normal controls. Recent studies have shown decreased vagal function in cardiac patients with depression as well as in depressed patients without cardiac illness. In this study, we compared 20 h awake and sleep heart period nonlinear measures using quantification of nonlinearity and chaos in two groups of patients with major depression and ischemic heart disease (mean age 59-60 years) before and after 6 weeks of treatment with paroxetine or nortriptyline. Patients received paroxetine, 20-30 mg/day or nortriptyline targeted to 190-570 nmol/l for 6 weeks. For HRV analysis, 24 patients were included in the paroxetine treatment study and 20 patients in the nortriptyline study who had at least 20000 s of awake data. The ages of these groups were 60.4 +/- 10.5 years for paroxetine and 60.8 +/- 13.4 years for nortriptyline. There was a significant decrease in the largest Lyapunov exponent (LLE) after treatment with nortriptyline but not paroxetine. There were also significant decreases in nonlinearity scores on S(netPR) and S(netGS) after nortriptyline, which may be due to a decrease in cardiac vagal modulation of HRV. S(netGS) and awake LLE were the most significant variables that contributed to the discrimination of postparoxetine and postnortriptyline groups even with the inclusion of time and frequency domain measures. These findings suggest that nortriptyline decreases the measures of chaos probably through its stronger vagolytic effects on cardiac autonomic function compared with paroxetine, which is in agreement with previous clinical and preclinical reports. Nortriptyline was also associated with a significant decrease in nonlinearity scores, which may be due to anticholinergic and/or sympatholytic effects. As depression is associated with a strong risk factor for cardiovascular mortality, one should be careful about using any drug that adversely affects cardiac vagal function., (Copyright 2002 S. Karger AG, Basel)

Rationale: Recent literature emphasizes the utility of QT variability to study ventricular electrophysiologic function. In this investigation, we sought to test the hypothesis that beat-to-beat fluctuations in QT intervals are mediated by sympathetic activity in normal subjects using postural challenge and isoproterenol infusions., Subjects and Methods: We obtained ECG in the supine and standing postures during spontaneous breathing, at 12, 15 and 20 per minute controlled breathing (n = 19), and before and after infusions of isoproterenol, a beta-adrenergic agent, in the supine posture during spontaneous breathing (n = 11) using lead II configuration in healthy human adult subjects. Heart rate (HR) and QT time series data were analyzed by spectral analysis of 256 s of real-time data. Beat-to-beat QT intervals were measured by automated analysis of ECG. A QT variability index (QT(vi)) was calculated for each subject as the logarithm of the ratio of normalized QT variance to normalized HR variance. We also calculated fractal dimensions of QT time series during spontaneous breathing., Results: QT(vi) was significantly higher in the standing than in the supine posture (-1. 93 +/- 0.27 vs. -1.47 +/- 0.41; p = 0.0001), and also during isoproterenol infusions in the supine posture (-1.83 +/- 0.39 vs. -1. 27 +/- 0.43; p = 0.0001). Fractal dimensions of QT time series were also significantly higher during standing (p = 0.00001) and isoproterenol infusions (p = 0.0002). Respiratory rate or tidal volume did not account for the increased QT variability seen in the standing posture., Conclusions: A change from the supine to the standing posture as well as infusion of isoproterenol significantly increased the absolute as well as normalized QT variability, which appears to be due to an increase in sympathetic activity associated with these conditions., (Copyright 2000 S. Karger AG, Basel)

We investigated cardiac autonomic function in 16 patients with panic disorder before and after treatment with paroxetine using Holter ECG records. Our previous data suggest a relative increase in sympathetic activity in patients with panic disorder, especially during sleep. Data for 20 h and awake and sleep periods were analyzed using spectral analysis to quantify absolute and relative heart period variability in ultra low (ULF: <0.0033 Hz), very low (VLF: 0.0033-0.04 Hz), low (LF: 0.04-0.15 Hz) and high (HF: 0.15-0.5 Hz) frequency bands. We also obtained fractal dimensions (FD) for the 20-hour, awake and sleep time series of RR intervals. Paroxetine treatment (19.7 +/- 4.7 mg/day for 105 +/- 37 days) resulted in a significant improvement in the frequency and intensity of panic attacks and also on the state anxiety inventory. Paroxetine treatment produced a significant decrease of 20-hour absolute HF power, awake absolute LF power and sleep absolute HF power. There was also a significant decrease of FDs after treatment with paroxetine for the sleep period. The decrease in LF and HF powers, and sleep FD is likely due to the antimuscarinic effect of paroxetine. The decrease in day-time LF power may also be due to a decrease in relative cardiac sympathetic activity after paroxetine treatment.

Previous evidence suggests an increased cardiovascular morbidity in patients with panic disorder. In this study, we compared 24-hour ECG in patients with panic disorder (n = 22; age: 36.1 +/- 7.6 years) and healthy controls (n = 21; age: 34.6 +/- 10.0 years). The QTc intervals during the day or night were not significantly different between patients and controls. Ventricular ectopic beats were also not significantly different between the two groups. These results do not suggest any overt cardiac arrhythmias in this age group of patients with panic disorder.

Symptoms of anxiety suggest autonomic dysfunction and most of the psychotropic agents used to treat anxiety and affective disorders have strong autonomic effects. This article describes the utility and importance of analysis of heart rate and blood pressure time series to study cardiac autonomic function in psychiatric research. The variability of heart rate between 0.15 and 0.5 Hz is related to respiratory sinus arrhythmia, and is modulated by cholinergic activity in both supine and standing postures, while the variability between 0.04 and 0.15 Hz is dually influenced by cholinergic and adrenergic mechanisms which can be used as a relative measure of sympathetic activity in standing posture. Analysis of beat-to-beat control of heart rate and blood pressure gives important information about cardiac sympathetic and parasympathetic interaction, which could be used to study the possible link between anxiety and depressive disorders and increased cardiovascular morbidity.

Previous reports on heart rate variability suggest that, compared to controls, panic disorder patients have a higher relative mid-frequency (MF) (0.07-0.15 Hz) power in standing posture and that they also have a greater increase in standing MF power after the administration of yohimbine. We studied the effects of nortriptyline, a tricyclic antidepressant, on HR variability measures in 13 panic disorder patients before and after successful treatment. There was a highly significant increase in supine and standing HR (p = 0.00001) while there was a significant decrease of standing absolute and relative MF power (p = 0.009 and 0.0001 respectively). This uncontrolled preliminary study suggests a decrease in sympathetic activity related to nortriptyline treatment in addition to its anticholinergic effects.

Recently, heart rate (HR) variability has received considerable attention, and a decreased HR variability has been linked to a significant risk of cardiovascular illness. We have previously reported such a decreased variability in panic disorder patients. In this study, we report on HR variability in 12 depressed and 6 panic disorder patients at baseline and 1 and 3 weeks of treatment with imipramine as measured by the standard deviation, mean consecutive difference and the standard deviation of the mean consecutive difference of the R-R intervals in supine, supine deep breathing and standing postures. In all subjects, imipramine (mean dose: 70 mg/day) produced a significant decrease in heart rate variability at week 3 as measured by the above variables. This decrease in HR variability during imipramine treatment is probably due to its anticholinergic effects.

In a prospective study, we have compared R-axis on routine electrocardiograms of panic disorder patients (n = 52) with that of depressed patients (n = 41) and normal controls (n = 65). All subjects were physically healthy and were normotensive. There was a significant leftward shift of R-axis in both depressed and panic disorder patients compared to normal controls. The implications of these findings are discussed.

Jitteriness appears to be a specific side effect of tricyclic antidepressant treatment in panic disorder patients. In addition, the patients with jitteriness have lower serum iron levels compared to those that do not develop jitteriness (p = 0.01).

Supine and standing heart rate (HR) and blood pressure measures were compared among 19 nonsmoking normal controls, 29 smoking patients and 36 nonsmoking patients with panic disorder. The smoking patients had a significantly higher supine HR, standing diastolic blood pressure, standing mean blood pressure and supine and standing cardiac load measures compared to both patient nonsmokers and controls. There was no significant difference between controls and nonsmoking patients for any of the above measures except for the higher standing HR and the delta increase in HR upon standing in female panic disorder patients which suggests increased adrenergic activity. When lipid values of panic disorder patients (n = 92) were compared to National Reference Values for their sex and age for an increased risk of cardiovascular illness, there was no significant risk with regard to plasma levels of total cholesterol, high-density lipoprotein cholesterol or low-density lipoprotein cholesterol.

We compared the responses of bulimic subjects to those of panic disorder patients and normal controls during infusions of sodium lactate and isoproterenol in a double-blind, placebo-controlled study. Four of 8 bulimics infused with lactate had panic attacks. Three of 9 bulimics infused with isoproterenol panicked, and 1 bulimic panicked with a placebo infusion. Although bulimics were less likely than panic disorder patients to panic during provocative infusions, their anxiety levels as measured by a panic description scale were as great. A large portion of the anxiety response in bulimics occurred in those who had concurrent panic attacks.