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Usefulness of heart rate variability (HRV) for monitoring clozapine plasma levels

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... Clozapine is used only in patients who have failed to respond adequately to standard drug treatment of schizophrenia given for an adequate duration due to the risk of agranulocytosis and seizures. Differences in clinical response have been observed in schizophrenic patients given clozapine treatment and one of the potential reasons is pharmacokinetic variability (1,2). Many factors (i.e. ...
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Individual differences in the pharmacokinetics of clozapine in healthy Chinese adults Introduction: Differences in response to clozapine among patients have received considerable attention. Individual pharmacokinetic differences are a major reason. Objective: The aim of this study was to investigate the pharmacokinetic variability in the blood levels ofclozapine among young, healthy, Chinese male volunteers. Methods: A total of 18 volunteers who received 12.5mg of clozapine participated in the study. Blood samples were measured by using High-Performance Liquid Chromatography-Electrospray ionization tandem mass spectrometry (LC-MS/MS). The major pharmacokinetic parameters were calculated from the plasma concentration-time curve and individual variability was assessed. Results: The findings indicated that the AUC(0-48h), C-max and t(1/2) varied 2.9, 2.6, and 2.0 fold, respectively among the individuals even with similar physiological status. Conclusions: Individual differences were obvious among healthy volunteers and greater differences could have been observed if more subjects had been included in the study. Psychiatrists and pharmacists may need to have more patience and pay more attention to high variability in response to clozapine among schizophrenic patients with differences in weight, age, liver function, renal function, and pharmacogenetics.
... However, the effects of antipsychotics on HRV in patients with schizophrenia cannot be attributed simply to their receptor binding profile, as multiple other factors, such as disease processes, symptom severity, and adverse effects, also play a significant role in the complex regulation of HRV. 28 Therefore, further prospective investigations of the neurocardiac effects of various antipsychotics in patients with different clinical characteristics are required to better understand the complex interaction between antipsychotics and HRV. 19 In the present study, we did not perform actometry recordings to evaluate objective restlessness, since we focused on the subjective aspect of restlessness. ...
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Antipsychotic-induced subjective inner restlessness is one of the common and distressing adverse effects associated with antipsychotics; however, its underlying neurobiological basis is not well understood. We examined the relationship between antipsychotic-induced subjective inner restlessness and autonomic neurocardiac function. Twenty-two schizophrenia patients with antipsychotic-induced subjective restlessness, 28 schizophrenia patients without antipsychotic-induced subjective restlessness, and 28 matched healthy control subjects were evaluated. Assessments of the linear and nonlinear complexity measures of heart rate dynamics were performed. Multivariate analysis of variance and correlation analysis were conducted. The mean interbeat (RR) interval value was significantly higher in control subjects than in patients with and without antipsychotic-induced subjective restlessness (P < 0.05). The low frequency/high frequency ratio was significantly higher in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05), while the approximate entropy value was significantly lower in patients with antipsychotic-induced subjective restlessness than in control subjects and in patients without antipsychotic-induced subjective restlessness (P < 0.05). Correlation analyses controlling for psychotic symptom severity showed that the degree of antipsychotic-induced restlessness had a significant negative correlation with the value of approximate entropy (P < 0.05). The results indicate that antipsychotic-induced subjective restlessness is associated with altered heart rate dynamics parameters, particularly the nonlinear complexity measure, suggesting that it might adversely affect autonomic neurocardiac integrity. Further prospective research is necessary to elucidate the precise interrelationships and causality.
... 24 Evidence now exists for a strong association between reduced HRV and psychotropic drugs with anticholinergic properties includeing antipsychotics and tricyclic antidepressants. 4,891024,31 In addition, the effects of alpha adrenoceptor modulation on HRV via sympathetic and parasympathetic inputs were reported. 19,32,33 Therefore, a significant reduction in pNNx statistics is assumed to be explicitly as-sociated with the direct effects of clozapine, although the psychotic symptom itself, might contribute to the decreased heart rate dynamics. ...
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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. 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. 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)). 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.
Article
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.
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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.
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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.
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Psychotropic drugs are often liable to unwanted anticholinergic effects that reduce tolerance and compliance. Especially, in certain patient groups, such as elderly patients, anticholinergic adverse effects may be hazardous. There are also occasions in therapy when antimuscarinic activity is desired, e. g. in the treatment of neuroleptic-induced extrapyramidal symptoms with biperiden and other potent anticholinergic drugs. In this review, we describe various techniques to evaluate the anticholinergic influences of psychotropic drugs in vivo and also provide examples of previous human studies where these methods have been applied. By combining subjective ratings of anticholinergic effects to in vitro measurements of antimuscarinic activity in blood, as well as the functional state of salivary glands, sweat glands, heart and eye, a researcher can obtain a detailed anticholinergic profile of the drug in question, or a clinician can estimate the anticholinergic burden of his/her psychiatric patient who often uses multiple medications.
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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.
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In schizophrenics cardiovascular autonomic reactivity (CAR) can be used as an indicator of autonomic arousal. Using a standardized autonomic test battery (modified according to Ewing and Clarke) we prospectively compared the CAR between 46 actually ill schizophrenics (diagnosis according to DSM-III-R) treated with either haloperidol (n = 26) or clozapine (n = 20) and 30 well-matched healthy volunteers. Multivariate analysis demonstrated a significant effect of neuroleptic medication (haloperidol vs. clozapine) on heart rate and diastolic blood pressure under resting conditions as well as on the heart rate variance (30:15 ratio, deep-breathing, Valsalva) and blood pressure tests (sustained handgrip, Schellong). In addition a positive treatment response (using predefined outcome criteria of the Brief Psychiatric Rating Scale) was independently associated with lower resting heart rates and less impaired 30:15 ratios under neuroleptic medication. Our data indicate that clozapine treatment was associated with a substantial impairment of CAR, which can be explained by the drug's anticholinergic properties in combination with an increase in norepinephrine outflow. The greater heart rate variability in responders might be due to an early neuroleptic-induced decrease of sympathetic activity in the autonomic nervous system, which may precede clinical improvement. Our findings are discussed in relation to neuroleptic-induced changes in plasma catecholamine levels suggested to be useful biological markers in predicting treatment outcome.
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Abnormal autonomic activity in patients with schizophrenia has been reported, but how psychotic states influence the autonomic nervous system (ANS) has remained unclear due to methodological limitations. The influence of psychotic states on ANS activity in patients with schizophrenia was investigated using a recently developed method of analysis based on heart rate variability which assesses cardiac sympathetic and parasympathetic function separately. Cardiac autonomic function (CAF), together with psychotic states, was assessed at the beginning and the end of an 8-week study period in 53 patients with chronic schizophrenia. The CAF in age- and sex-matched control subjects was also examined. There were no significant differences between the patients and the control subjects in the mean R-R interval (RRI) or in the indices of the sympathetic and the parasympathetic function. In the patients who changed in psychotic states, the parasympathetic index was significantly decreased without significant changes in the sympathetic index when their psychotic states were more pronounced, suggesting psychotic states suppressed the parasympathetic function without affecting the sympathetic function. In these patients, the mean RRI was smaller when their psychotic states were more pronounced. Our results demonstrate that psychotic states affect the ANS, suggesting a relationship between cerebral cognitive and peripheral ANS activities, and that this is presumably mediated through the parasympathetic nervous system. These findings are discussed in comparison with previous reports on the CAF in schizophrenia.
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Drug monitoring in psychiatry usually serves psychoactive drug plasma concentration measurement. Anticholinergic properties offer a faster approach to monitoring pharmacodynamic intraindividual effects of the drug by measuring their effects on heart rate variability (HRV), which is sympathetically and parasympathetically controlled via cholinergic synapses. The plasma concentrations of the atypical antipsychotics clozapine and olanzapine correlated with parameters of HRV in 59 patients suffering from schizophrenia or schizoaffective disorder. HRV during 4 minutes at rest was extracted from the ECG trace of a routine digital EEG registration in addition to blood sampling for plasma concentration measurement (HPLC method). We calculated sympathetically and parasympathetically controlled heart frequency bands (low, medium and high frequency) and other HRV parameters, coefficient of variation (CV), and root mean square of successive differences (RMSSD). All HRV parameters were significantly more impaired in clozapine patients (n = 33, mean clozapine plasma concentration 331 +/- 294 ng/ml) than in olanzapine patients (n = 26, mean olanzapine plasma concentration 42 +/- 32 ng/ml) and demonstrated 1.7 - 4.8 times the cardiac anticholinergic properties of clozapine in vivo. 14 out of 14 patients with a CV beyond 3.2 % had clozapine plasma concentrations below the proposed optimal therapeutic concentration of 350 ng/ml. All HRV parameters were inversely and significantly correlated with the clozapine plasma concentrations (such as lgCV: r = - 0.73, p < 0.001) and, to a lesser extent, with the olanzapine plasma concentrations (lgCV r = - 0.44, p < 0.05). These results underline the potential clinical value of HRV parameter extraction from routine ECGs in predicting plasma concentrations and objective individual neurocardiac effects of drugs with anticholinergic properties.