Sang Hoon Yi

Heart rate dynamics and their relationship to psychotic symptom severity in clozapine-treated schizophrenic subjects.

The analysis of heart rate variability (HRV) has proven to be useful in evaluating the neuroautonomic dysfunctions associated with various clinical conditions. The purpose of this study was to investigate the linear and non-linear dynamic measures of HRV, and to evaluate their relationship with the psychotic symptom severity, in clozapine-treated schizophrenic subjects. Fifty schizophrenic patients treated with clozapine as monotherapy and 50 normal control subjects were evaluated for HRV analysis. The HRV measurements were obtained from a 30-min resting electrocardiogram (ECG). The severity of psychotic symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS). In the patient group, the complexity and symbolic dynamics measures as well as the time and frequency domain measures of HRV were significantly lower than in the control group (P<0.01). The intermediate-term fractal scaling component value was significantly higher in the patient group (P<0.01). The PANSS total score and the positive symptom subscale score had significant negative correlations with the sample entropy (SampEn) value (P<0.01). In conclusion, schizophrenic patients treated with clozapine had markedly different heart rate dynamics compared to normal control subjects. The severity of psychotic symptoms was associated with the SampEn value, suggesting that the non-linear complexity measure might be useful in assessing the neuroautonomic dysfunction in schizophrenia.

Differential pattern of heart rate variability in patients with schizophrenia.

The cardiac autonomic dysfunction has been reported in patients with schizophrenia. Heart rate variability (HRV) provides non-invasive indices of cardiac autonomic modulation. This study examined whether patients with schizophrenia may show a distinctive pattern of HRV compared to healthy controls. Nine measures of time, frequency and complexity domains were extracted from 5-min resting evaluation of HRV in 30 unmedicated patients with schizophrenia and 30 age- and gender-matched controls. In addition to inferential statistics, a hierarchical clustering (HC) was used to examine difference in the interrelationships among HRV measures between the two groups. Multivariate analysis of variance revealed a significant group effect. Significantly lower sample entropy (SampEn) and a trend towards a higher ratio of low- to high frequency (LF/HF) were observed in the schizophrenia group. In the results of HC using Wards method, SampEn co-clustered with LF/HF ratio in patients with schizophrenia compared to the separation of LF/HF ratio in healthy controls. In concert with decreased parasympathetic activity, low complexity of heart rate dynamics may reduce adaptability of cardiovascular system to changes in internal or external environment, thus increasing the risk of cardiovascular events. Diverse HRV measures combined in a multivariate fashion appear to be useful in understanding the pattern of neurocardiac modulation in patients with schizophrenia.

Changes in heart rate dynamics of patients with schizophrenia treated with risperidone.

Neurocardiac dysregulation has been reported in schizophrenia. Indices of heart rate variability (HRV) are useful in assessing the status of cardiac autonomic regulation. We explored within-subject changes in HRV indices in acutely ill patients with schizophrenia treated with risperidone. Sixteen medication-naïve or medication-free patients with DSM-IV schizophrenia completed electrocardiogram (ECG) assessments at baseline and after six weeks of treatment with risperidone. Indices of HRV were extracted from 5-min resting ECG recordings and compared to those obtained from control subjects matched for age and gender. Psychiatric and drug-induced extrapyramidal symptoms were assessed by the Positive and Negative Syndrome Scale (PANSS) and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS). In comparison with matched controls, patients with acute schizophrenia showed lower values of time-domain measures, lower high-frequency power (HF) and a higher ratio of low to high frequency (LF/HF). In the within-subject analyses, a significant decrease in LF/HF was associated with risperidone treatment. In addition, LF/HF, which initially co-clustered with clinical variables, congregated with other HRV measures after the six-week risperidone treatment. These results indicate that, in the therapeutic process, risperidone treatment may exert a beneficial influence on the sympathovagal imbalance in acute schizophrenia.

An integrative assessment of the psychophysiologic alterations in young women with recurrent major depressive disorder.

Objective Alterations in neuroelectrical activities coincide with major depressive disorder (MDD). This study examines the pattern of cerebral activity and cardiac autonomic parameters of euthymic women with recurrent MDD. Methods Resting electroencephalograms and electrocardiograms were recorded from 20 women with MDD receiving escitalopram and 40 matched and healthy women. We computed frontal alpha asymmetry to evaluate the interhemispheric balance. Parameters of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy was used to assess the complexity of neurocardiac dynamics. The relationship between cardiovagal activity and alpha electroencephalogram was examined with a coherence analysis. Results Multivariable analysis of variance revealed a differential pattern of psychophysiologic variables between MDD patients and controls (p = .03). MDD was associated with a tendency toward lower left frontal activity (−0.06 [standard deviation = 0.14] versus 0.04 [0.17] ln&mgr;V2, p = .04). Discriminant analysis demonstrated more right frontal activation, a lower high-frequency heart rate power spectrum, and a higher ratio of the low- to high-frequency heart rate power spectrum in patients with MDD compared with controls. Residual depressive symptoms (r = −0.09 to 0.11, p = .63–.99) and escitalopram dosage (r = −0.09 to 0.28, p = .22–.84) were not correlated with autonomic measures. Coherence between normalized high-frequency component of the heart rate power spectrum and alpha power was not significant (F3, p = .27; F4, p = .16). Conclusions Euthymic women with recurrent MDD have a distinctive psychophysiologic profile. This profile may reflect altered frontal activation and a reduced cardiovagal tone in depression. Abbreviations MDD = major depressive disorder EEG = electroencephalogram HRV = heart rate variability ECG = electrocardiogram HDRS = Hamilton Depression Rating Scale SSRI = selective serotonin reuptake inhibitor EOG = electrooculogram RR = beat to beat NN = normal to normal LF = low-frequency component of the heart rate power spectrum HF = high-frequency component of the heart rate power spectrum SampEn = sample entropy MANCOVA = multivariate analysis of covariance

Patterns of cardiorespiratory coordination in young women with recurrent major depressive disorder treated with escitalopram or venlafaxine.

Evidence from previous studies suggests autonomic dysregulation in patients with major depressive disorder (MDD). Antidepressant treatment may also affect central autonomic function. We investigated whether the type of antidepressant might be associated with the pattern of cardiorespiratory coordination in non-depressed women with recurrent MDD. Resting electrocardiograms and respiratory signals were simultaneously recorded from 38 euthymic women with recurrent MDD who were treated with either escitalopram (n=19) or venlafaxine (n=19) monotherapy and from 38 healthy women. Linear measures of heart rate variability were extracted to assess cardiac autonomic control. Sample entropy (SampEn) was computed to assess the complexity of heart rate and respiratory signals, and cross-SampEn was calculated to measure the nonlinear interaction of both signals. Significant decreases in the cardiovagal tone and cardiorespiratory coupling of women with recurrent MDD receiving venlafaxine, and tendencies toward lower cardiovagal tone and cardiorespiratory coupling in women with recurrent MDD receiving escitalopram were observed when compared with healthy controls. Effect sizes for these differences were large between women receiving venlafaxine and healthy controls. We found a positive association between cardiorespiratory decoupling and venlafaxine dose. Norepinephrine-enhancement, within a therapeutic dose range, seems to be closely associated with decreased vagal tone and reduced nonlinear coupling between heart rate and respiration in euthymic women with recurrent MDD. However, the effects of serotonin enhancement on cardiovagal tone should be considered. Our results suggest that the pharmacodynamic properties of antidepressants may affect autonomic regulation of women with recurrent MDD even in euthymic state.

The pNNx Heart Rate Variability Statistics: An Application to Neuroautonomic Dysfunction of Clozapine-Treated Subjects

Objective The percentage of successive normal cardiac interbeat intervals greater than 50 msec (pNN50) is a widely used heart rate variability measure, which is useful in identifying the neuroautonomic dysfunction of psychiatric disorders. However, pNN50 is only one member of a larger family of pNNx statistics, where x is greater than 0 msec. The potential application of the general pNNx statistics has not yet been explored in the psychiatric field. The authors examined the pNNx statistics in clozapine-treated subjects and normal controls to evaluate the usefulness of the general pNNx statistics. Methods Sixty-one schizophrenic patients treated with clozapine and fifty-nine normal controls were evaluated. Probability values for the differences between the groups at each pNN value (range: pNN1-pNN100) were calculated using data obtained from a 30-minute electrocardiogram. Results The conventional pNN50 and pNNx values with x<50 msec were all significantly lower in the patient group (p<0.05). The distinction between the two groups was more prominent at pNN values less than 50 msec than that observed at pNN50. The maximum separation between groups occurred at pNN5 (68.2±19.1 vs. 22.5±20.5, p<10-22). Conclusion The pNNx with x<50 msec provided more robust discrimination between the groups than the conventional pNN50, suggesting the importance of analyzing very small variations of interbeat interval in discriminating normal and pathological heart rate patterns. The results also suggest that the general pNNx statistics may be applied and useful in evaluating the neuroautonomic dysfunction in patients treated with clozapine, complementing the traditionally computed pNN50 value.

Automatic detection of seizure termination during electroconvulsive therapy using sample entropy of the electroencephalogram.

Determining the exact duration of seizure activity is an important factor for predicting the efficacy of electroconvulsive therapy (ECT). In most cases, seizure duration is estimated manually by observing the electroencephalogram (EEG) waveform. In this article, we propose a method based on sample entropy (SampEn) that automatically detects the termination time of an ECT-induced seizure. SampEn decreases during seizure activity and has its smallest value at the boundary of seizure termination. SampEn reflects not only different states of regularity and complexity in the EEG but also changes in EEG amplitude before and after seizure activity. Using SampEn, we can more precisely determine seizure termination time and total seizure duration.

Effects of clozapine on heart rate dynamics and their relationship with therapeutic response in treatment-resistant schizophrenia.

Abstract Previous studies have suggested the utility of nonlinear complexity measures of heart rate variability (HRV) in evaluating the regulatory capacity of the neuroautonomic system. The purpose of the present study was to investigate the effects of clozapine on the nonlinear complexity measures of HRV in patients with treatment-resistant schizophrenia to find novel electrophysiological markers that indicate response to clozapine treatment. Forty patients with treatment-resistant schizophrenia were evaluated during 8 weeks of clozapine monotherapy. For nonlinear complexity measures of HRV, the approximate entropy (ApEn) and sample entropy (SampEn) values were obtained. The response rate to clozapine was 37.5%. The results of multivariate analysis of covariance revealed that the ApEn and the SampEn values of HRV at week 8 were significantly higher in the responders than in the nonresponders. Repeated-measures analysis of covariance showed a significant group by time interaction effect in the ApEn and SampEn indices. The responder group showed an increasing pattern of change in these complexity measures after administration of clozapine, whereas the nonresponder group showed a decreasing pattern of change. These results suggest that the nonlinear dynamic complexity measures of HRV, which indicate the irregularity and complexity of the biosystem, may be useful in evaluating the therapeutic changes of neuroautonomic function in schizophrenia. The response to clozapine treatment is expected to be more favorable when the plasticity of the neuroautonomic system reflected in the nonlinear complexity measures is high.

Diminished neurocardiac dynamics associated with antipsychotic-induced extrapyramidal syndrome.

The relationship between antipsychotic-induced extrapyramidal syndrome (EPS) and the autonomic neurocardiac function was examined in 57 schizophrenic patients treated with atypical antipsychotics. Comprehensive assessments of EPS and heart rate dynamics were performed. There was a significant negative correlation of non-hypokinetic parkinsonism, akathisia, and dyskinesia with several linear and novel non-linear heart rate dynamics measures, suggesting reduced neurocardiac dynamics associated with some forms of EPS. Assessment of heart rate dynamics may be useful for the detection of these adverse effects and may serve as a useful non-invasive method providing a dynamic window into the alterations of complex neuronal activity.

T224. THE FUNCTIONAL CONNECTIVITY DERIVED WITH BIVARIATE ANALYSIS, COHERENCE AND PHASE LOCKING VALUE IN PATIENTS WITH SCHIZOPHRENIA UNDER CLOZAPINE

Abstract Background Coherence (COH) and Phase Locking Value (PLV) may have considerable potentials for investigating anomalies of functional connectivity in schizophrenia but results are still conflicting. This study is aimed to investigate relationships between plasma levels of clozapine (p-CZP) and norclozapine (p-NCZP), and total and cognitive factor scores of Positive and Negative Syndrome Scale (PANSS-T, -C), and functional connectivity by COH and PLV. Methods Fifty-eight patients who were diagnosed as schizophrenia with DSM-5 criteria and under CZP were recruited (duration of illness, 15.5 ± 8.0 years; duration of CZP, 6.8 ± 4.6 years; mean daily dose of CZP, 233.6 ± 88.4 mg). COH and PLV were calculated with Neurophysiological Biomarker Toolbox from qEEG and were averaged from the signals of electrodes in the designated brain regions, frontal (F), temporal (T), central (C) and occipitoparietal (OP). For interhemispheric connectivity, electrodes except all midline channels were combined into Odd (O) and Even (E). The results were presented at ≥0.30 of Spearman correlation. Results 1) Correlation coefficient between p-CZP and p-NCZP was 0.84, and those of CZP dose with p-CZP and p-NCZP were 0.38 and 0.53, respectively. 2) p-CZP showed correlations with OCEC in delta and alpha, OTEC in delta, OCEOP in theta, OTEF in alpha, and OOPEF in gamma band in COH, and OOPEOP in beta band in PLV. 3) p-NCZP showed correlations with ETEOP in delta, theta, and gamma, OCEC in delta and alpha, OFOC and OCEOP in delta, OFET and OTET in alpha, OCEF in beta, OOPEC in gamma band in COH, and with ETEOP in delta, theta, and beta, OTET and OCEC in alpha, OCEF in beta band in PLV. 4) CZP dose showed correlations with ETEC in beta and gamma, ETEOP in theta, OCEF in alpha, OTET in beta, OOPEF and OOPET in gamma band in COH, and with OTET in alpha and beta, ETEOP in theta, OTEOP in alpha, ETEC in beta, OFOC in gamma band in PLV. 5) PANSS-T showed correlations with OFEOP and EFEOP in alpha, OCEOP in beta, OTOC and OTEF in gamma band in COH, and with OTEF in beta and gamma, OFET in delta, OOPEF in beta, OTOC and OCEOP in gamma band in PLV. 6) PANSS-C showed correlations with EFEOP in delta, theta, alpha, and beta, OOPEOP in delta, alpha, and beta, OFET and OTEF both in alpha and beta, OOPEF in delta, OFEOP in alpha, OFEC and OCEOP in beta, OTOC in gamma band in COH, and with EFEOP in theta, alpha, and beta, OFEOP and OOPEOP both in alpha and beta, OFET in delta and beta, OTOC, OOPEF, OOPEOP in beta, OTOC and OCEOP in PLV. 7) PANSS-T and -C showed no correlations with p-CZP, p-NCZP and CZP dose. 8) However, the clinical and drug variables showed significant simultaneous correlation with certain functional connectivity, but sometimes the direction correlation was opposite. Discussion The relationship between functional connectivity and clozapine parameters seems to demonstrate inter- and intra-hemispheric connections in brain regions. However, there were same and/or opposite directions of correlations between COH and PLV dependent EEG band frequencies and clinical and drug variables. Taken together, investigating the functional connectivity with COH and PLV could give the information about p-CZP and p-NCZP before the laboratory reports, the degree of psychopathology in patients with schizophrenia under CZP, and the differentiations of surface symptoms whether derived from pathophysiology of schizophrenia or from clozapine effects.