Twenty-Four-Hour QT Interval Variability: Increased QT Variability during Sleep in Patients with Panic Disorder

Yeragani, Vikram K.; Pohl, Robert; Balon, Richard; Jampala, V.C.; Jayaraman, Anusha

doi:10.1159/000063568

Cited by 32 publications

(24 citation statements)

References 35 publications

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“…First, an elevated QTVi and elevated NE spillover have been independently found in postinfarction patients and in patients with PD and depression (2,20,22,25). Second, activation of cardiac sympathetic activity (by orthostatic challenge or isoproterenol infusion) leads to increase in QTVi (23).…”

Section: Discussionmentioning

confidence: 99%

QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder

Baumert¹,

Lambert²,

Dawood³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Nalivaiko E. QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder. Am J Physiol Heart Circ Physiol 295: H962-H968, 2008. First published July 3, 2008 doi:10.1152/ajpheart.00301.2008.-Suggestions were made that increased myocardial sympathetic activity is reflected by elevated QT variability (dynamic changes in QT interval duration). However, the relationship between QT variability and the amount of norepinephrine released from the cardiac sympathetic terminals is unknown. We thus attempted to assess this relationship. The study was performed in 17 subjects (12 with major depressive disorder and 5 with panic disorder). Cardiac norepinephrine spillover (measured by direct catheter technique coupled with norepinephrine isotope dilution methodology) was assessed before and 4 mo after treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants. The distribution of the cardiac norepinephrine spillover was bimodal, with the majority of patients having values of Յ10 ng/min. There was a positive correlation between cardiac norepinephrine spillover and corrected QT interval (r ϭ 0.7, P ϭ 0.03) but not with any of the QT variability measures. However, in a subgroup of five patients who had high levels of cardiac norepinephrine spillover (Ͼ20 ng/min) a tendency for a strong positive correlation with variance of QT intervals (r ϭ 0.9, P ϭ 0.08) was observed. There were significant correlations between the severity of depression and QT variability indexes normalized to the heart rate [QTVi and QT interval/R-R interval (QT/RR) coherence] and between the severity of anxiety and the QT/RR residual and regression coefficient, respectively. Treatment with SSRI antidepressants substantially reduced depression score but did not affect any of the QT variability indexes. We conclude that in depression/panic disorder patients with near-normal cardiac norepinephrine levels QT variability is not correlated with cardiac norepinephrine spillover and is not affected by treatment with SSRI. sympathetic activity; antidepressants AN EXCESSIVE CARDIAC SYMPATHETIC activity is a recognized risk factor for cardiac morbidity and mortality. In a range of clinical contexts, elevated cardiac sympathetic outflow has been demonstrated to contribute to ventricular arrhythmias (10), sudden death (6), myocardial stunning (21), and left ventricular hypertrophy (19). Direct assessment of norepinephrine (NE) spillover (the "gold standard" for assessing cardiac sympathetic activity) is a complex, invasive procedure, and cardiac sympathetic activity is still most frequently assessed by measuring mean heart rate or assessing its dynamic variability (1). Obviously, heart rate reflects autonomic influences only at the level of the cardiac pacemaker region. Because different regions of the heart could be under independent autonomic control (7, 12, 13), it becomes increasingly evident that indexes reflecting sympathetic influences in the ventricular myocardium might be of better predictive and ...

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Section: Discussionmentioning

confidence: 99%

QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder

Baumert¹,

Lambert²,

Dawood³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…[55][56][57][58][59] Circadian rhythm is characteristic for QTc as well. [60][61][62][63][64][65][66] Figure 4 shows pooled, individually corrected (as described earlier) QT intervals before treatment vs the clock time in 26 unrelated healthy individuals from the previously presented data.…”

Section: Circadian Rhythm In Qt and Qtcmentioning

confidence: 99%

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Piotrovsky¹

2005

AAPS J

109

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A BSTRACTIn this review, factors affecting the QT interval and the methods that are currently in use in the analysis of drug effects on the QT interval duration are overviewed with the emphasis on (population) pharmacokinetic-pharmacodynamic (PK-PD) modeling. Among which the heart rate (HR) and the circadian rhythm are most important since they may interfere with the drug effect and need to be taken into account in the data analysis. The HR effect or the RR interval (the distance between 2 consecutive R peaks) effect is commonly eliminated before any further analysis, and many formulae have been suggested to correct QT intervals for changes in RR intervals. The most often used are Bazett and Fridericia formulae introduced in 1920. They are both based on the power function and differ in the exponent parameter. However, both assume the same exponent for different individuals. More recent fi ndings do not confi rm this assumption, and individualized correction is necessary to avoid under-or overcorrection that may lead to artifi cial observations of drug-induced QT interval prolongation. Despite the fact that circadian rhythm in QT and QTc intervals is a welldocumented phenomenon, it is usually overlooked when drug effects are evaluated. This may result in a false-positive outcome of the analysis as the QTc peak due to the circadian rhythm may coincide with the peak of the drug plasma concentration. In view of these effects interfering with a potential drug effect on the QTc interval and having in mind low precision of QT interval measurements, a preferable way to evaluate the drug effect is to apply a population PK-PD modeling. In the literature, however, there are only a few publications in which population PK-PD modeling is applied to QT interval prolongation data, and they all refer to antiarrhythmic agents. In this review, after the most important sources of variability are outlined, a comprehensive population PK-PD model is presented that incorporates an individualized QT interval correction, a circadian rhythm in the individually corrected QT intervals, and a drug effect. The model application is illustrated using real data obtained with 2 compounds differing in their QT interval prolongation potential. The usefulness of combining data of several studies is stressed. Finally, the standard approach based on the raw observations and formal statistics, as described in the Preliminary Concept paper of the International Conference on Harmonization, is briefl y compared with the method based on population PK-PD modeling, and the advantages of the latter are outlined.

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“…Effective anti-panic treatment has been suggested to increase heart rate variability (Garakani et al 2008;Tucker et al 1997), and may thus potentially decrease the risk of cardiac mortality. Studies have also found increased QT variability in PD patients (Sullivan et al 2004;Yeragani et al 2002a;Yeragani et al 2000), reflecting an abnormal ventricular repolarisation, which may lead to malignant ventricular arrhythmias and sudden cardiac death (Adamson and Vanoli 2001). …”

Section: Somatic -Cardiacmentioning

confidence: 99%

Paroxetine influences respiration in rats: implications for the treatment of panic disorder

Olsson¹,

Annerbrink²,

Bengtsson³

et al. 2004

European Neuropsychopharmacology

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SwedenPrinted by Chalmers Reproservice, Göteborg, Sweden Previously published papers were reproduced with kind permission from the publishers. Background and aims: Panic disorder is a psychiatric disorder characterized by sudden attacks of intense anxiety. It displays a lot of features suggesting that it may be associated with an underlying aberration in the autonomic regulation of heart activity and respiration: i) the attacks are often characterized by respiratory symptoms and symptoms from the heart, ii) the attacks can be elicited by respiratory stimulants, iii) between attacks, patients with panic disorder often display enhanced respiratory variability and reduced heart rate variability, and iv) patients with panic disorder display enhanced prevalence of respiratory disorders and enhanced mortality in cardiovascular disease. Addressing the reasons for these physiological aberrations may help in elucidating the pathophysiology underlying panic disorder, and shed light on why this disorder is associated with enhanced mortality in cardiovascular disease. Serotonin is believed to be a neurotransmitter of great importance for panic disorder, as well as for the regulation of respiration: one main purpose of the animal studies presented in this thesis hence was to increase our knowledge regarding the role of serotonin in respiratory regulation, the hypothesis being that aberrations in respiration may cause the anxiety attacks, and that serotoninmodulating drugs may prevent panic attacks partly by stabilizing the regulation of respiration. In the first part of the thesis, data is presented on the effects on respiration in freely moving rats of various serotonergic compounds. The second part of this thesis is focused on genetic variations that may be associated with panic disorder. Orexin is a neuropeptide of suggested importance for both respiratory regulation and arousal. We investigated two polymorphisms in the orexin receptors 1 and 2, HCRTR1 Ile408Val and HCRTR2 Val308Iso, in panic disorder patients and healthy controls. Catechol-O-methyltransferase (COMT) is an enzyme that degrades catecholamines such as dopamine and noradrenaline, and may thus be of importance for both autonomic control and psychiatric symptoms. The functional Val158Met polymorphism in this gene has been associated with panic disorder in several studies; in an attempt to replicate this finding, we genotyped this polymorphism in the same group of panic disorder patients. In a separate cohort, we also explored if the same polymorphism is associated with risk factors for cardiovascular disease. Observations: 1) Serotonin depletion with para-chlorophenylalanine decreased respiratory rate and increased respiratory variability. 2) Chronic treatment with serotonin reuptake inhibitors increased respiratory rate. 3) Acute treatment with serotonin reuptake inhibitors, as well as the serotonin releasing drugs d-fenfluramine and m-CPP, and the 5-HT1A antagonist WAY-100635, decreased respiratory rate. 4) The HCRTR2 Val308Iso polymorphism was significantly...

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Twenty-Four-Hour QT Interval Variability: Increased QT Variability during Sleep in Patients with Panic Disorder

Cited by 32 publications

References 35 publications

QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder

QT interval variability and cardiac norepinephrine spillover in patients with depression and panic disorder

Pharmacokinetic-pharmacodynamic modeling in the data analysis and interpretation of drug-induced QT/QTc prolongation

Paroxetine influences respiration in rats: implications for the treatment of panic disorder

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