Manuel E. Tancer

Nonlinear measures of respiration: Respiratory irregularity and increased chaos of respiration in patients with panic disorder

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 (1,024 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.

Normal urinary free cortisol and postdexamethasone cortisol in social phobia: comparison to normal volunteers

In primates, social stress is associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis. Social phobia is a common, often disabling, form of pathological anxiety characterized by marked distress in situations involving possible scrutiny or evaluation. Little is known about HPA function in patients with social phobia. We examined 24-hour excretion of urinary free cortisol (UFC) in 54 patients with social phobia and post-dexamethasone cortisol levels in 64 patients with social phobia and found no evidence of HPA-axis overactivity compared to normal controls, despite pathological levels of anxiety.

Major depression in patients with panic disorder: factors associated with course and recurrence

The relationship between anxiety and depressive disorders has been the subject of considerable interest and controversy. In this study, the occurrence and course of affective illness was systematically examined in 63 patients meeting DSM-III-R criteria for panic disorder. Forty (63%) of the patients had experienced at least one major depressive episode. Of these, 13 (32.5%) experienced their first depressive episode prior to the onset of panic disorder, 15 (37.5%) experienced their first depressive episode after the onset of panic disorder, and in 12 (30.0%) the onset of the disorders was concurrent. Patients with agoraphobia had comparable rates of depression (68%) to patients without agoraphobia (53%, P = NS), and they had similar temporal patterns of depressive illness. Comorbidity with social phobia was associated with an increased longitudinal likelihood of major depression compared to patients without this comorbid diagnosis (P less than 0.05). Patients with longer duration of illness, early onset depression, melancholic depression, or family histories of anxiety or depression had an increased likelihood of having experienced recurrent depression. These findings are discussed in the context of current theories regarding the development of affective illness in patients with anxiety disorders.

Clomipramine challenge responses covary with Tridimensional Personality Questionnaire scores in healthy subjects

Cloningers Unified Biosocial Theory of Personality postulates a relationship between the relative functional activity of central serotonergic, dopaminergic, and noradrenergic neurotransmitter systems, and the strength of three elemental dimensions of personality. These dimensions are Harm Avoidance, Novelty Seeking, and Reward Dependence, respectively. Accordingly, we predicted that neuroendocrine responses to serotonergic challenge would correlate with Harm Avoidance scores, but not with Novelty Seeking or Reward Dependence scores. We examined the relationship between the prolactin and cortisol responses to a 12.5-mg intravenous clomipramine challenge and these personality dimensions as measured by Cloningers Tridimensional Personality Questionnaire in 32 healthy subjects. The cortisol response correlated only with Harm Avoidance scores, as predicted; however, prolactin response did not correlate with Harm Avoidance scores. Instead, it demonstrated an inverse relationship with Novelty Seeking scores. There was a positive relationship of baseline prolactin with Harm Avoidance in a post hoc analysis. Cortisol response to serotonergic challenge may be a better indicator for responsivity of serotonergic systems as they relate to the personality dimension of Harm Avoidance than is prolactin. Prolactin responses may be overly affected by dopaminergic influences; however, baseline prolactin may still be a valid indicator of serotonergic tone.

Influence of olanzapine on QT variability and complexity measures of heart rate in patients with schizophrenia.

Previous studies have shown that untreated patients with acute schizophrenia present with reduced heart rate variability and complexity as well as increased QT variability. This autonomic dysregulation might contribute to increased cardiac morbidity and mortality in these patients. However, the additional effects of newer antipsychotics on autonomic dysfunction have not been investigated, applying these new cardiac parameters to gain information about the regulation at sinus node level as well as the susceptibility to arrhythmias. We have investigated 15 patients with acute schizophrenia before and after established olanzapine treatment and compared them with matched controls. New nonlinear parameters (approximate entropy, compression entropy, fractal dimension) of heart rate variability and also the QT-variability index were calculated. In accordance with previous results, we have observed reduced complexity of heart rate regulation in untreated patients. Furthermore, the QT-variability index was significantly increased in unmedicated patients, indicating increased repolarization lability. Reduction of the heart rate regulation complexity after olanzapine treatment was seen, as measured by compression entropy of heart rate. No change in QT variability was observed after treatment. This study shows that unmedicated patients with acute schizophrenia experience autonomic dysfunction. Olanzapine treatment seems to have very little additional impact in regard to the QT variability. However, the decrease in heart rate complexity after olanzapine treatment suggests decreased cardiac vagal function, which may increase the risk for cardiac mortality. Further studies are warranted to gain more insight into cardiac regulation in schizophrenia and the effect of novel antipsychotics.

Rearing conditions alter social reactivity and D1 dopamine receptors in high- and low-aggressive mice

As a result of selective breeding, NC900 mice exhibit isolation-induced attacks in a social interaction test, whereas NC100 mice do not attack but freeze instead. Administration of the D1 receptor agonist dihydrexidine was previously shown to reduce aggression in NC900 mice and nonagonistic approaches in NC100 mice. This resulted from induction of a marked social reactivity in both selected lines. Because isolation rearing also induces social reactivity, the present experiment was designed to test the hypothesis that D1 dopamine receptors mediate isolation-induced social reactivity. Isolation was expected to potentiate the effects of a D1 agonist and to increase D1 dopamine receptor density. Thus, isolated and group-reared mice were administered dihydrexidine, and their social behavior was compared to vehicle-injected controls. Dihydrexidine induced higher levels of reactivity among isolated than among group-reared animals, especially in NC900 mice. In independent experiments, increased densities of D1 dopamine receptors in the striatum of isolated animals were found, with no change in affinity. These studies suggest an important role for the D1 dopamine receptor as a mediator of isolation-induced social reactivity.

Paroxetine decreases respiratory irregularity of linear and nonlinear measures of respiration in patients with panic disorder: A preliminary report

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.

Normal serum cholesterol in panic disorder

In this report, we assessed serum cholesterol levels in 80 patients with panic disorder and 80 normal controls. Because cholesterol levels are age- and gender-dependent, the groups were matched for age and gender

Effects of thyrotropin-releasing hormone on blood pressure and heart rate in phobic and panic patients : a pilot study

Several lines of evidence suggest that patients with anxiety disorders have heightened autonomic responsiveness compared to controls. For example, psychophysiological measures, such as electrodermal activity, remain elevated longer in patients with anxiety disorders compared to controls (for review see Hoehn-Saric and McLeod 1988). Ambulatory heart rate and blood pressure monitoring in patients with panic disorder have revealed elevations in blood pressure and heart rate during panic attacks (Freedman et al. 1985; White and Baker 1986!. In addition to its we~-known neuroendocrine stimulatory effect~ (A~;derson et al. 1971), the hypothalamic tr~peptide thyrotropin-releasing hormone (TRH) has rapid (1.~2 minute), marked effects on both blood pressure and heart rate (Borowski et al. 1984; Zaloga et al. 1984). This response closely parallels the time-course of crescendo changes in autonomic function often observed during spontaneous (Lader and Mathews 1970) or chemically induced panic attacks. This phenomenological overlap led us to investigate

Exaggerated Beat-to-Beat R Amplitude Variability in Patients with Panic Disorder after Intravenous Isoproterenol

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 β-adrenergic stimulation on R and T amplitude variability in panic disorder patients by infusing the β-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 (Rvm and Tvm) and the Rvi and Tvi, 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 β-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 β-adrenergic effects of isoproterenol or to isoproterenol-induced anxiety.