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Effects of Clozapine on Heart Rate Dynamics and Their Relationship With Therapeutic Response in Treatment-Resistant Schizophrenia

Kim, Jong-Hoon MD, PhD*; Yi, Sang Hoon PhD; Lee, Jinyoung BA*; Kim, Yong Sik MD, PhD‡§

Journal of Clinical Psychopharmacology: February 2013 - Volume 33 - Issue 1 - p 69–73
doi: 10.1097/JCP.0b013e31827d14e3
Brief Reports

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.

From the *Department of Psychiatry, Gil Hospital, Gachon University of Medicine and Science, Incheon; †Department of Computer Aided Science, Institute of Basic Sciences, Inje University, Gimhae; ‡Department of Psychiatry, Seoul National University College of Medicine, Seoul; and §Department of Psychiatry, Dongguk University Ilsan Hospital, Goyang, Korea.

Received February 10, 2012; accepted after revision May 29, 2012.

Reprints: Jong-Hoon Kim, MD, PhD, Department of Psychiatry, Gil Hospital, Gachon University of Medicine and Science, 1198 Guwol-Dong, Namdong-Gu, Incheon 405-760, Korea (e-mail

This work was supported in part by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A070001) and by the Gil Hospital Research Fund (Dr J-H Kim).

© 2013 Lippincott Williams & Wilkins, Inc.