RSS-Feed abonnieren
DOI: 10.1055/s-2002-31520
Heart-Rate Variability (HRV) in the ECG Trace of Routine EEGs: Fast Monitoring for the Anticholinergic Effects of Clozapine and Olanzapine?
Publikationsverlauf
Publikationsdatum:
23. Mai 2002 (online)
![](https://www.thieme-connect.de/media/pharmaco/200203/lookinside/thumbnails/10.1055-s-2002-31520-1.jpg)
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.
References
- 1 Agelink M W, Majewski T, Wurthmann C, Lukas K, Ullrich H, Linka T, Klieser E. Effects of newer atypical antipsychotics on autonomic neurocardiac function: a comparison between amisulpride, olanzapine, sertindole, and clozapine. J Clin Psychopharmacol. 2001; 21 8-13
- 2 Bablenis E, Weber S S, Wagner R L. Clozapine: a novel antipsychotic agent. DICP. 1989; 23 109-115
- 3 Baldessarini R J, Frankenburg F R. Clozapine. A novel antipsychotic agent [see comments]. N Engl J Med. 1991; 324 746-754
- 4 Berntson G G, Bigger-JT J, Eckberg D L, Grossman P, Kaufmann P G, Malik M, Nagaraja H N, Porges S W, Saul J P, Stone P H, van-der-Molen M W. Heart rate variability: origins, methods, and interpretive caveats. Psychophysiology. 1997; 34 623-648
- 5 Berntson G G, Cacioppo J T, Quigley K S. Autonomic cardiac control. I. Estimation and validation from pharmacological blockades. Psychophysiology. 1994; 31 572-585
- 6 Berntson G G, Stowell J R. ECG artifacts and heart period variability: don't miss a beat!. Psychophysiology. 1998; 35 127-132
- 7 Bymaster F P, Calligaro D O, Falcone J F, Marsh R D, Moore N A, Tye N C, Seeman P, Wong D T. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology. 1996; 14 87-96
- 8 Bymaster F P, Nelson D L, DeLapp N W, Falcone J F, Eckols K, Truex L L, Foreman M M, Lucaites V L, Calligaro D O. Antagonism by olanzapine of dopamine D1, serotonin2, muscarinic, histamine H1 and alpha 1-adrenergic receptors in vitro. Schizophr Res. 1999; 37 107-122
- 9 Cacioppo J T, Berntson G G, Binkley P F, Quigley K S, Uchino B N, Fieldstone A. Autonomic cardiac control. II. Noninvasive indices and basal response as revealed by autonomic blockades. Psychophysiology. 1994; 31 586-598
- 10 Chengappa K N, Pollock B G, Parepally H, Levine J, Kirshner M A, Brar J S, Zoretich R A. Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine. J Clin Psychopharmacol. 2000; 20 311-316
- 11 Eschweiler G W, Nickola M, Scheffer F, Bartels M, Waxmann G, Gaertner I. Heart rate variability and plasma concentrations of clozapine and olanzapine. World Psychiatric Association. 1999; II 57
- 12 Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988; 45 789-796
- 13 Kronig M H, Munne R A, Szymanski S, Safferman A Z, Pollack S, Cooper T, Kane J M, Lieberman J A. Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry. 1995; 152 179-182
- 14 Lieberman J A, Kane J M, Johns C A. Clozapine: guidelines for clinical management [see comments]. J Clin Psychiatry. 1989; 50 329-338
- 15 Miller D D, Fleming F, Holman T L, Perry P J. Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry. 1994; 55 (B) 117-121
- 16 Perry P J, Miller D D, Arndt S V, Cadoret R J. Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients. Am J Psychiatry. 1991; 148 231-235
- 17 Rechlin T. Decreased R-R variation: a criterium for overdosage of tricyclic psychotropic drugs. Intensive Care Med. 1995; 21 598-601
- 18 Rechlin T, Beck G, Weis M, Kaschka W P. Correlation between plasma clozapine concentration and heart rate variability in schizophrenic patients. Psychopharmacology Berl. 1998; 135 338-341
- 19 Rechlin T, Claus D, Weis M. Heart rate variability in schizophrenic patients and changes of autonomic heart rate parameters during treatment with clozapine. Biol Psychiatry. 1994; 35 888-892
- 20 Rechlin T, Orbes I, Weis M, Kaschka W P. Autonomic cardiac abnormalities in alcohol-dependent patients admitted to a psychiatric department. Clin Auton Res. 1996; 6 119-122
- 21 Rechlin T, Weis M, Claus D, Kaschka W P. Identifying delirious states and autonomic cardiovascular dysfunction associated with amitriptyline treatment by standardized analysis of heart rate. Psychiatry Res. 1995; 56 279-287
- 22 Stevens I, Gaertner H J. Plasma level measurement in a patient with clozapine intoxication [letter]. J Clin Psychopharmacol. 1996; 16 86-87
- 23 Zahn T P, Pickar D. Autonomic effects of clozapine in schizophrenia: comparison with placebo and fluphenazine. Biol Psychiatry. 1993; 34 3-12
- 24 Ziegler D, Laux G, Dannehl K, Spuler M, Muhlen H, Mayer P, Gries F A. Assessment of cardiovascular autonomic function: age-related normal ranges and reproducibility of spectral analysis, vector analysis, and standard tests of heart rate variation and blood pressure responses. Diabet Med. 1992; 9 166-175
- 25 Ziegler D, Piolot R, Strassburger K, Lambeck H, Dannehl K. Normal ranges and reproducibility of statistical, geometric, frequency domain, and non-linear measures of 24-hour heart rate variability. Horm Metab Res. 1999; 31 672-679
G. W. Eschweiler
Department of Psychiatry and Psychotherapy, University of Tübingen
Osianderstrasse 24
72076 Tübingen
Germany
eMail: eschweiler@med.uni-tuebingen.de