- Email: [email protected]
Heart rate variability before and after treatment with electroconvulsive therapy
Journal of Affective Disorders 44 (1997) 13–20
Research report
Heart rate variability before and after treatment with electroconvulsive therapy a, b c Susan K. Schultz *, Erling A. Anderson , Philippe van de Borne a
Department of Psychiatry, University of Iowa, College of Medicine and Veterans Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 2242, USA b Department of Anesthesia, University of Iowa College of Medicine and Veterans Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 52242, USA c Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center 200 Hawkins Drive, Iowa City, IA 52242, USA Received 8 October 1996; accepted 30 January 1997
Abstract It has been suggested that depression may be associated with decreased parasympathetic activity. Based on this work, we tested the hypothesis that treatment of depression with electroconvulsive therapy (ECT) would result in a relative increase in cardiac vagal (parasympathetic) activity. Changes in respiratory sinus arrhythmia, a marker of cardiac parasympathetic activity, were examined in nine patients with depressive episodes before and after ECT using spectral analysis. Hamilton Depression Rating Scale scores decreased significantly. In terms of the heart rate measures, RR interval tended to decrease and the amplitude of respiratory sinus arrhythmia decreased significantly following the course of ECT. This reduction in respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability. Additionally, the magnitude of symptom improvement as measured by the Hamilton Scale correlated with the decrease in amplitude of the respiratory sinus arrhythmia. We report that treatment of depression with ECT was associated with a relative decrease in parasympathetic activity, in contrast to our initial hypothesis of a relative increase. This finding may not be related to the ECT per se but rather to the resolution of depression, as there was a significant correlation between the decrease in Hamilton Depression Rating Scale scores and decrease in parasympathetic activity. Further work is necessary to better understand the autonomic changes associated with depressive illness and the clinical risks and benefits associated with various treatment modalities. 1997 Elsevier Science B.V. Keywords: Heart rate variability; Depression; Autonomic activity; Parasympathetic tone; Electroconvulsive therapy
1. Introduction In recent years, attention has focused on the *Corresponding author. Tel.: 1 1 319 3563869; fax: 1 1 319 3562587; e-mail: [email protected].
potential impact of major depressive disorder on mortality rates due to cardiovascular disease. Several researchers (Barefoot et al., 1996; Frasure-Smith, 1991; Frasure-Smith et al., 1993; Rabins et al., 1985) have documented that depression independently predicts increased mortality in post-myocardial infarc-
0165-0327 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved PII S0165-0327( 97 )01443-2
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S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
tion patients even after controlling for severity of cardiac impairment. Additionally, in patients without documented cardiovascular illness, the presence of depression has been shown to predict future morbidity and mortality from cardiac causes (Ahern et al., 1990; Anda et al., 1993; Costa, 1987; Frasure-Smith, 1991; Garrity and Klein, 1975). It has been further postulated that one underlying factor contributing to this increase in mortality may be a decrease in parasympathetic activity (Bigger et al., 1992; Singer et al., 1988). One means of assessing parasympathetic activity is through the measurement of heart rate variability (HRV). Decreased heart rate variability has been shown to be an independent predictor of mortality in post-myocardial infarction patients and in patients with congestive heart failure and other cardiopulmonary illnesses (Kleiger et al., 1987). Early studies of HRV in depressive illness measured variability in the time domain only, i.e. evaluated the variation in time between successive RR intervals (RRI). One such study used a 24-h continuous electrocardiogram recording to compare depressed patients to non-depressed controls. This study noted decreased R–R variability among all intervals greater than 50 ms in the depressed patients, which was interpreted as a decrement in parasympathetic tone (Dalack and Roose, 1990). In contrast, other studies using time domain measures have not distinguished differences between depressed patients and controls (Yeragani et al., 1991). Thus the question of whether changes in parasympathetic activity occur with depression has largely remained unanswered. More recent studies, using power spectral analysis have been able to more fully characterize the various frequency constituents hidden in the HRV signal and are able to distinguish cyclic variations specifically associated with parasympathetic input to the heart. The RR interval discloses these variations related to the respiratory cycle called respiratory sinus arrhythmia, a measure of high frequency (HF) variability. Respiratory sinus arrhythmia manifests as a decrease in RRI during inspiration and an increase during expiration, reflecting the magnitude of cardiac vagal (parasympathetic) activity (Akselrod et al., 1981; Eckberg, 1983; Katona and Jih, 1975). Despite the more specific measures afforded by
spectral analysis, studies of patients with depression have been confounded by the impact of antidepressant medications which may substantially influence HRV measures. Specifically, the anticholinergic sideeffects of tricyclic antidepressant medications have been implicated the primary source of decreased HRV findings in major depression (Jakobsen et al., 1984; Rechlin et al., 1994a,b; Yeragani et al., 1992). One study by Rechlin et al. compared depressed patients before and after treatment with amitriptyline or paroxetine. This study noted that prior to treatment, HRV measures in the patients did not differ from healthy controls. After two weeks of medication the amitriptyline-treated patients had decreased HRV, while paroxetine-treated patients did not. This study suggested that treatment of depression with paroxetine (a selective serotonin reuptake inhibitor) does not appear to affect parasympathetic tone (Rechlin et al., 1994b). However, symptomatic improvement was not analyzed in relation to HRV, so this study was only able to draw conclusions about medication effects and did not address effects attributable to change in depressive illness. Another study by the same group did address depression severity. Rechlin et al. studied patients with major depression and patients with dysthymia who had undergone treatment with amitriptyline (Rechlin, 1994). The patients with major depression displayed a decrease in high frequency variability (consistent with a loss of parasympathetic activity) compared to the dysthymic patients, suggesting that the increased severity of illness associated with major depression may be accompanied by a greater loss of parasympathetic activity. However, both the major depressive and dysthymic patients in this study received amitriptyline, which confounded the assessment of parasympathetic control. The study reported here incorporated ‘before and after’ measures of depression severity using the Hamilton Depression Rating Scale and measures of HRV in patients undergoing treatment with ECT. The use of ECT avoided the confounding anticholinergic effects of tricyclic antidepressants and provided a relatively short response period with a high success rate. It was hypothesized that depression would be associated with decreased cardiac vagal activity initially, which would then increase following a course of treatment. Changes in respiratory sinus
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
arrhythmia, a marker of cardiac parasympathetic activity (Akselrod et al., 1981; Eckberg, 1983; Katona and Jih, 1975), were assessed in nine patients with depressive episodes.
2. Methods Nine patients hospitalized at the University of Iowa psychiatric inpatient units participated in this study. These subjects represented consecutive referrals for treatment of a depressive episode with ECT. All subjects gave informed consent prior to participation in this study. Inclusion criteria required the presence of a major depressive episode with or without psychotic features. Subjects with cardiovascular disease such as previous myocardial infarction or documented atherosclerotic disease were excluded, as were patients with diabetes, asthma or other medical condition known to affect autonomic function. Patients receiving tricyclic antidepressants were excluded. Some patients were receiving non-tricyclic psychotropic medications such as selective serotonin reuptake inhibitors (e.g. paroxetine) throughout the course of treatment, however these were the same both before and after treatment. All subjects underwent a Hamilton Rating Scale before and after treatment with ECT. The protocol for this study was approved by the institutional review board at the University of Iowa. All participants were studied in the Human Cardiovascular Physiology Laboratory of the Department of Cardiology, University of Iowa, Iowa City. After initial assessment by a research psychiatrist and administration of the Hamilton Depression Rating Scale, the subjects underwent a thirty minute pre-treatment assessment as follows: Respiration was measured using an inductance plethysmograph, and a continuous electrocardiogram was obtained using standard chest leads (Biotach and Pneumotrace, Gould Electronics, Valley View, OH). Electrocardiogram and respiration were recorded on an IBM 433DX / T computer. All subjects were breathing spontaneously and were not allowed to speak during the study. Measurement of heart rate variability was analyzed via power spectral analysis. Spectral analysis was restricted to the respiratory and RRI artifact-
15
free segments (150–300 s). Analog-to-digital conversion was performed on-line at 1000 samples / s for the electrocardiogram and at 200 samples / s for respiration. The time series of the respiratory and RRI were viewed to be originated from non-equidistant sampled underlying signals, and a discrete Fourier transformation was applied for computing the resulting spectra using the CARSPAN 1.0 program (Mulder, 1992; Mulder et al., 1987; Robbe et al., 1987). Power spectral values in the HF band (0.15–0.40 Hz) determined the amplitude of respiratory sinus arrhythmia. We also determined the absolute power in the total spectrum (0.02–0.50 Hz). Because the physiological significance of the low frequency variability of RRI is controversial (Task Force, 1996), this paper will focus solely on the HF measures. The above measures were obtained initially after completion of Hamilton Ratings and preceding the first ECT. The measures were then obtained a second time after the subject had finished a course of sufficient duration as determined by the non-research clinical inpatient team as to either fully treat the depressive episode or to confer maximal benefit. The subjects were reassessed one day after completion of ECT with the power spectral analysis described above. The psychiatrist determining the Hamilton Depression Rating Scores before and after treatment was blind to the HRV measures and similarly the variability measures were obtained in a blinded fashion to the extent of depression severity. All patients received ECT on a schedule of three times per week with a constant current bidirectional square wave stimulus device (MECTA Model SR-1) (MECTA Corporation). The leads were placed bilaterally in the standard bifrontotemporal position. Stimuli were initiated using standard settings (1.0 ms pulse width, 40 Hz frequency and 1.0 s duration). Stimuli were titrated to seizure threshold at the first treatment. Seizure duration was between 30 and 40 s for the majority of treatments. Both motor convulsive movements using a cuff technique and electroencephalogram monitoring were used to assess seizure duration. Seizure duration exceeding 20 s was considered adequate. Subjects were administered the following agents intravenously: glycopyrrolate 0.2 mg, methohexital (0.75 mg / kg) and succinylcholine (0.6 mg / kg). The glycopyrrolate is an
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S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
anticholinergic (antimuscarinic) agent used as a preanaesthetic to control secretions and optimize airway management during ECT. The duration of the anticholinergic effect is short (peaks within 30–45 min) and vagal blocking effects are of short duration (Ali-Melkila et al., 1993). Two of the nine subjects also received intravenous esmolol 30 mg, an ultrashort acting beta-blocker. Like the glycopyrrolate, esmolol was used for management of acute treatment effects. Esmolol has a half-life of only 9 min and would be expected to have no sustained cardiac effects following its elimination (Barbier et al., 1995). To avoid the confounding effects of these agents on parasympathetic measures, all subjects underwent the second HRV measures the following day (24–36 hours) following their last ECT. The data were not normally distributed and statistical analysis consisted of two-tailed Wilcoxon tests and Spearman correlation coefficients corrected for ties. Values are expressed as means6standard error of the mean. Significance was assumed at the p , 0.05 level.
Table 1 Depression ratings and subject characteristics Sex
Age
[ of treatments
Hamilton Score Pre-ECT
Hamilton Score Post-ECT
M F M F F M F F F
31 44 19 53 43 38 61 47 41
6 7 6 11 6 12 9 9 7
54 35 38 30 28 22 44 44 21
21 5 1 3 7 9 9 18 11
10206326 ms 2 to 2716159 ms 2 , p 5 0.008). This reduction in the amplitude of respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability after ECT (from 26916892 ms 2 to 6756284 ms 2 p 5 0.03) (Fig. 1). Additionally, the magnitude of improvement in depressive symptoms as measured by the Hamilton Depression Rating Scale was positively correlated with the decrement in HF variability (Spearman rho 5 0.75, p 5 0.03) (Fig. 2).
3. Results The sample consisted of 9 patients diagnosed with major depressive disorder. In one case there was thought to be a possible comorbid diagnosis of schizophrenia, in another there was a history of alcohol abuse in remission. However, all patients met cross-sectional criteria for DSM-IV Major Depressive Episode. The mean age of the sample was 42.2612.2 years. The mean years of education was 12.463.3. The subjects had been hospitalized a mean of 4.262.7 previous times. All but one patient had had at least one previous episode of depression and the current episode had been present at least two weeks in all cases. Four of the subjects had undergone previous courses of ECT in the past. Please see Table 1 for more information on individual subjects. All patients were noted to have decrements in Hamilton Depression Rating Scales scores. The Hamilton Depression Rating Scale decreased from 3464 to 1162 ( p 5 0.008). RR interval tended to decrease after ECT (from 864645 ms to 770632 ms, p 5 0.17) and ECT markedly decreased the amplitude of respiratory sinus arrhythmia (from
4. Discussion In this study, we measured parasympathetic activity utilizing spectral analysis before and after ECT. Previous work has suggested that parasympathetic activity may be decreased in patients with major depression compared to non-depressed controls (Dalack and Roose, 1990; Rechlin, 1994; Rechlin et al., 1994c; Roose et al., 1991). Based on these findings, we hypothesized that treatment of depression with ECT would result in increased measures of parasympathetic tone compared to pre-treatment measures. In contrast to our proposed hypothesis, we found that treatment of depression with ECT was associated with a decrease in amplitude of the respiratory sinus arrhythmia, i.e. decreased parasympathetic activity. There are a number of reasons why this investigation differs from other studies which have assessed HRV in depression. Some previous studies have examined parasympathetic activity in a crosssectional manner comparing subjects with major
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
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Fig. 1. The first graph depicts the change in the mean R-R interval (ms) before and after electroconvulsive therapy. The second demonstrates the change in the mean total power of the R-R interval (ms 2 ) and the third graph depicts the change in the high frequency power of the R-R interval (ms 2 ) before and after electroconvulsive therapy.
Fig. 2. The change in Hamilton Depression Rating Scores is shown in relationship to the change in high frequency power of the R-R interval (ms 2 ).
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S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
depression to non-depressed controls or to patients with other diagnoses such as panic disorder (Yeragani et al., 1995, 1991). In the case of panic disorder, cross-sectional studies may be very useful, as panic disorder has been characterized as a state of chronically upregulated sympathetic activity, i.e. a trait-like phenomenon. Major depression is distinctly different by virtue of its episodic nature, so HRV measures may be dependent on the state of the depression at the specific time in which they are obtained. This may be the source for the variation in findings in HRV and depression studies. It is also possible that the use of ECT may have introduced an unanticipated confounding influence on parasympathetic activity. The transient autonomic effects of seizure induction involve an initial parasympathetic release followed by an increase in sympathetic activity, though these effects are confined to the time period immediately surrounding the treatment and post-ictal recovery phase (Gaines and Rees, 1992). For this reason we avoided the immediate recovery phase and obtained the follow-up measures on the day following the final treatment. However, it is possible that there could be some degree of sustained effects either from the seizure or the anesthetic medications used during the treatment that could persist more than 24 h following the last treatment, though this does not appear likely. In terms of neurotransmitter changes following ECT, studies examining CSF dopamine, serotonin and norepinephrine metabolites have not been successful in delineating a specific pattern or direction of change (Abrams and Essman, 1976; Jori et al., 1975; Nordin et al., 1971). It has also been noted that transient elevations in LH, FSH, GH and prolactin may occur, yet this does not have any known clinical significance (Skrabanek et al., 1981; Whalley et al., 1982). This study is clearly limited to addressing only the observed changes in parasympathetic tone in depressed patients following ECT. Because we did not examine a non-ECT treated depressed group for comparison or a non-depressed group receiving ECT, we are not able to make assertions regarding the relative influences of changes in depression per se versus the effects of ECT. Although the mechanism responsible for our observations is not known, this
study suggests that treatment of depression with ECT may be associated with cardiac vagal withdrawal (i.e. decreased parasympathetic activity) in some patients. A more thorough understanding of the autonomic effects of ECT may yield clinical useful insights. Particularly as ECT is often used in the treatment of elderly patients, a group at risk for cardiovascular disease, with the assumption that antidepressant medications may be more problematic in terms of cardiac side effects. If ECT is indeed associated with a decrement in parasympathetic tone, this may represent a risk factor for cardiac mortality particularly if applied to a group prone to cardiovascular illness (Singer et al., 1988). However, recent studies have shown that ECT may be used with relative safety even in populations with cardiovascular disease (Rice et al., 1994; Zielinski et al., 1993). Our study examined only subjects without known cardiovascular disease and did not assess outcome measures such as cardiac morbidity, so we cannot speak to this issue. Yet it is possible that a subgroup of cardiac patients may be vulnerable to increased morbidity in the face of a decrement in parasympathetic tone and would represent a group at particular risk for ECT complications. As ECT will continue to be used in persons with substantial medical comorbidity and with disproportionately greater frequency in persons over the age of 65 (Thompson et al., 1994), the pursuit of a better understanding of its autonomic effects seems a worthwhile endeavor. There is still an enormous amount of information to be learned about the mechanisms underlying the both efficacy and complications of ECT. Studies such as this may provide insights for larger controlled investigations.
References Abrams, R. and Essman, W.B. (1976) Concentration of 5-hydroxyindolacetic acid, homovanillic acid and tryptophan in the cerebrospinal fluid of depressed patients before and after ECT. Biol. Psychiatry 11, 85–91. Ahern, D.K., Gorkin, L., Anderson, J.L., et al. (1990) Biobehavioral variables and mortality or cardiac arrest in the cardiac arrhythmia pilot study. Am. J. Cardiol. 66, 59–62. Akselrod, S., Gordon, D., Ubel, F.A., Shannon, C., Barger, A.C.
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20 and Cohen, R.J. (1981) Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science Wash. DC 213, 220–2. Ali-Melkila, T., Kanto, J. and Iisalo, E. (1993) Pharmacokinetics and related pharmacodynamics of anticholinergic drugs. Acta Anaestiologica Scandinavica 37, 633–42. Anda, R.J., Williamson, D., Jones, D., et al. (1993) Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 4, 285–294. Barbier G.H., Shettigar U.R. and Appunn D.O. (1995) Clinical rationale for use of an ultrashort acting beta blocker esmolol. Int. J. Clin. Pharmacol. Therapeut. 33, 212–8. Barefoot, J.C., Helms, M.J. and Mark, D.B. (1996) Depression and long-term mortality risk in patients with coronary artery disease. Am. J. Cardiol. 78, 613–617. Bigger, J.T.., Fleiss, J.L.., Steinman, R.C., Rolnitzky, L.M., Kleiger, R.E. and Rottman, J.N. (1992) Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 85, 164–171. Costa, P.T. (1987) Influence of the normal personality dimension of neuroticism on chest pain symptoms and coronary artery disease. Am. J. Cardiol. 60, 20J–26J. Dalack, G.W. and Roose, S.P. (1990) Perspectives on the relationship between cardiovascular disease and affective disorder. J. Clin. Psychiatry 51, 4–9. Eckberg, D.L. (1983) Human sinus arrhythmia as an index of cardiac outflow. J. Appl. Physiol. 54, 961–966. Frasure-Smith, N. (1991) In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men. Am. J. Cardiol. 67, 121–127. Frasure-Smith, N., Lesperance, F. and Talajic, M. (1993): Depression following myocardial infarction. J. Am. Med. Assoc. 270, 1819–1825. Gaines, G.Y. and Rees, D.I. (1992) Anesthetic considerations for electroconvulsive therapy. Southern Med. J. 85, 469–82. Garrity, T.F., Klein, R.F. (1975) Emotional response and clinical severity as early determinants of six-month mortality after myocardial infarction. Heart and Lung 4, 730–737. Jakobsen, J., Hauksson, P., Vestergaard, P. (1984) Heart rate variation in patients treated with antidepressants. An index of anticholinergic effects? Psychopharmocol. 84, 544–548. Jori, A., Dolfini, A. and Casati, C. (1975) Effect of ECT and imiparmine treatment on the concentration of 5-hydroxyindolacetic acid (5HIAA) and homovanillic acid (HVA) in the cerebrospinal fluid of depressed patients. Psychopharmacologia 44, 87–93. Katona, P.G., Jih, F. (1975) Respiratory sinus arrhythmia: Noninvasive measure of parasympathetic control. J. Appl. Physiol. 39, 801–805. Kleiger, R.E., Miller, J.P., Bigger, J.T. and Moss, A.J. (1987) Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am. J. Cardiol. 59, 256–262. . Lake Oswego and Oregon. MECTA Corporation. Lake Oswego, Oregon. Mulder, L.J.M. (1992) Measurement and analysis methods of
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heart rate and respiration for use in applied environments. Biol. Psychol. 34, 205–236. Mulder, L.J.M., Van Dellen, H., Van der Meulen, P., Opheikens, B. (1987) CARSPAN: A spectral analysis program for cardiovascular time series. In: FJ, Maarse, LJM Mulder J Sjouw, AE Akkerman (Eds), Proceedings of the Second Workshop on Computers in Psychology. Lisse: Swets en Zeitlinger, pp 30– 38. Nordin, G., Ottosson, J.O. and Roos, B.E. (1971) Influence of convulsive therapy on 5-hydroxyindolacetic acid and homovanillic acid in cerebrospinal fluid in endogenous depression. Psychopharmacologia 20, 315–20. Rabins, P.V., Harvis, K. and Koven, S. (1985) High Fatality rates of late-life depression associated with cardiovascular disease. J. Affective Disord. 9, 165–167. Rechlin, T. (1994) Decreased parameters of heart rate variation in amitriptyline treated patients: Lower parameters in melancholic depression than in neurotic depression—a biological marker? Biol. Psychiatry 36 705–707. Rechlin, T., Claus, D., Weis, M. (1994a) Heart rate analysis in 24 patients treated with 150 mg amitriptyline per day. Psychopharmacology 116, 110–114. Rechlin, T., Weis, M. and Claus, D. (1994b) Heart rate variability in depressed patients and differential effects of paroxetine and amitriptyline on cardiovascular autonomic functions. Pharmacopsychiatry 27, 124–128. Rechlin, T., Weis, M., Spitzer A. and Kaschka, W.P. (1994c) Are affective disorders associated with alterations of heart rate variability? J. Affective Disord. 32, 271–275. Rice, E.H., Sombrotto, L.B. and Markowitz, J.C. (1994) Cardiovascular morbidity in high-risk patients during ECT. Am. J. Psychiatry 151, 1637–1641. Robbe, H.W., L.J., M, Ruddel, H., Langewitz, W.A., Veldman, J.B., Mulder, G. (1987) Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10, 538–543. Roose, S.P. and Dalack, G.W., (1991) Death, depression, and heart disease. J. Clin. Psychiatry 52, 34–39. Singer, D.H., Martin, G.J., Magid, N., et al. (1988) Low heart rate variability and sudden cardiac death. J. Electrocardiol. Suppl, s46–s55. Skrabanek, P., Balfe, A. and Webb, M. (1981) Electroconvulsive Therapy (ECT) increases the plasma growth hormone, prolactin, lutenizing hormone, and follicle-stimulating hormone but not thyrotropin or substance P. Psychoneuroendocrinol. 6, 261– 70. Task Force (1996) Task force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology; Heart rate variability: Standards of measurement, physiological interpretation, and clinical use. Circulation 93, 1043–1065. Thompson, J.W., Wiener, R.D. and Myers, C.P. (1994) Use of ECT in the United States in 1975, 1980 and 1986. Am. J. Psychiatry 151, 1657–1661. Whalley, L., Dick, H. and Watts, A.G. (1982) Immediate increases in plasma prolactin and neurophysin but not other hormones after electroconvulsive therapy. Lancet 2, 1064.
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Yeragani, V.K., Balon, R., Polf, R., and Ramesh, C. (1995) Depression and Heart Rate Variability. Biological Psychiatry 38, 768–770. Yeragani, V.K., Pohl, R., Balon, R., et al. (1991) Heart rate variability in patients with major depression. Psychiatry Res. 37, 35–46.
Yeragani, V.K., Pohl, R., Balon, R., et al. (1992) Effect of imipramine treatment on heart rate variablility measures. Neuropsychobiology 26, 27–32. Zielinski, R.J., Roose, S.P. and Devanand, D.P. (1993) Cardiovascular complications of ECT in depressed patients with cardiac disease. Am. J. Psychiatry 150, 904–909.
Research report
Heart rate variability before and after treatment with electroconvulsive therapy a, b c Susan K. Schultz *, Erling A. Anderson , Philippe van de Borne a
Department of Psychiatry, University of Iowa, College of Medicine and Veterans Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 2242, USA b Department of Anesthesia, University of Iowa College of Medicine and Veterans Affairs Medical Center, 200 Hawkins Drive, Iowa City, IA 52242, USA c Department of Internal Medicine, University of Iowa College of Medicine and Veterans Affairs Medical Center 200 Hawkins Drive, Iowa City, IA 52242, USA Received 8 October 1996; accepted 30 January 1997
Abstract It has been suggested that depression may be associated with decreased parasympathetic activity. Based on this work, we tested the hypothesis that treatment of depression with electroconvulsive therapy (ECT) would result in a relative increase in cardiac vagal (parasympathetic) activity. Changes in respiratory sinus arrhythmia, a marker of cardiac parasympathetic activity, were examined in nine patients with depressive episodes before and after ECT using spectral analysis. Hamilton Depression Rating Scale scores decreased significantly. In terms of the heart rate measures, RR interval tended to decrease and the amplitude of respiratory sinus arrhythmia decreased significantly following the course of ECT. This reduction in respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability. Additionally, the magnitude of symptom improvement as measured by the Hamilton Scale correlated with the decrease in amplitude of the respiratory sinus arrhythmia. We report that treatment of depression with ECT was associated with a relative decrease in parasympathetic activity, in contrast to our initial hypothesis of a relative increase. This finding may not be related to the ECT per se but rather to the resolution of depression, as there was a significant correlation between the decrease in Hamilton Depression Rating Scale scores and decrease in parasympathetic activity. Further work is necessary to better understand the autonomic changes associated with depressive illness and the clinical risks and benefits associated with various treatment modalities. 1997 Elsevier Science B.V. Keywords: Heart rate variability; Depression; Autonomic activity; Parasympathetic tone; Electroconvulsive therapy
1. Introduction In recent years, attention has focused on the *Corresponding author. Tel.: 1 1 319 3563869; fax: 1 1 319 3562587; e-mail: [email protected].
potential impact of major depressive disorder on mortality rates due to cardiovascular disease. Several researchers (Barefoot et al., 1996; Frasure-Smith, 1991; Frasure-Smith et al., 1993; Rabins et al., 1985) have documented that depression independently predicts increased mortality in post-myocardial infarc-
0165-0327 / 97 / $17.00 1997 Elsevier Science B.V. All rights reserved PII S0165-0327( 97 )01443-2
14
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
tion patients even after controlling for severity of cardiac impairment. Additionally, in patients without documented cardiovascular illness, the presence of depression has been shown to predict future morbidity and mortality from cardiac causes (Ahern et al., 1990; Anda et al., 1993; Costa, 1987; Frasure-Smith, 1991; Garrity and Klein, 1975). It has been further postulated that one underlying factor contributing to this increase in mortality may be a decrease in parasympathetic activity (Bigger et al., 1992; Singer et al., 1988). One means of assessing parasympathetic activity is through the measurement of heart rate variability (HRV). Decreased heart rate variability has been shown to be an independent predictor of mortality in post-myocardial infarction patients and in patients with congestive heart failure and other cardiopulmonary illnesses (Kleiger et al., 1987). Early studies of HRV in depressive illness measured variability in the time domain only, i.e. evaluated the variation in time between successive RR intervals (RRI). One such study used a 24-h continuous electrocardiogram recording to compare depressed patients to non-depressed controls. This study noted decreased R–R variability among all intervals greater than 50 ms in the depressed patients, which was interpreted as a decrement in parasympathetic tone (Dalack and Roose, 1990). In contrast, other studies using time domain measures have not distinguished differences between depressed patients and controls (Yeragani et al., 1991). Thus the question of whether changes in parasympathetic activity occur with depression has largely remained unanswered. More recent studies, using power spectral analysis have been able to more fully characterize the various frequency constituents hidden in the HRV signal and are able to distinguish cyclic variations specifically associated with parasympathetic input to the heart. The RR interval discloses these variations related to the respiratory cycle called respiratory sinus arrhythmia, a measure of high frequency (HF) variability. Respiratory sinus arrhythmia manifests as a decrease in RRI during inspiration and an increase during expiration, reflecting the magnitude of cardiac vagal (parasympathetic) activity (Akselrod et al., 1981; Eckberg, 1983; Katona and Jih, 1975). Despite the more specific measures afforded by
spectral analysis, studies of patients with depression have been confounded by the impact of antidepressant medications which may substantially influence HRV measures. Specifically, the anticholinergic sideeffects of tricyclic antidepressant medications have been implicated the primary source of decreased HRV findings in major depression (Jakobsen et al., 1984; Rechlin et al., 1994a,b; Yeragani et al., 1992). One study by Rechlin et al. compared depressed patients before and after treatment with amitriptyline or paroxetine. This study noted that prior to treatment, HRV measures in the patients did not differ from healthy controls. After two weeks of medication the amitriptyline-treated patients had decreased HRV, while paroxetine-treated patients did not. This study suggested that treatment of depression with paroxetine (a selective serotonin reuptake inhibitor) does not appear to affect parasympathetic tone (Rechlin et al., 1994b). However, symptomatic improvement was not analyzed in relation to HRV, so this study was only able to draw conclusions about medication effects and did not address effects attributable to change in depressive illness. Another study by the same group did address depression severity. Rechlin et al. studied patients with major depression and patients with dysthymia who had undergone treatment with amitriptyline (Rechlin, 1994). The patients with major depression displayed a decrease in high frequency variability (consistent with a loss of parasympathetic activity) compared to the dysthymic patients, suggesting that the increased severity of illness associated with major depression may be accompanied by a greater loss of parasympathetic activity. However, both the major depressive and dysthymic patients in this study received amitriptyline, which confounded the assessment of parasympathetic control. The study reported here incorporated ‘before and after’ measures of depression severity using the Hamilton Depression Rating Scale and measures of HRV in patients undergoing treatment with ECT. The use of ECT avoided the confounding anticholinergic effects of tricyclic antidepressants and provided a relatively short response period with a high success rate. It was hypothesized that depression would be associated with decreased cardiac vagal activity initially, which would then increase following a course of treatment. Changes in respiratory sinus
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
arrhythmia, a marker of cardiac parasympathetic activity (Akselrod et al., 1981; Eckberg, 1983; Katona and Jih, 1975), were assessed in nine patients with depressive episodes.
2. Methods Nine patients hospitalized at the University of Iowa psychiatric inpatient units participated in this study. These subjects represented consecutive referrals for treatment of a depressive episode with ECT. All subjects gave informed consent prior to participation in this study. Inclusion criteria required the presence of a major depressive episode with or without psychotic features. Subjects with cardiovascular disease such as previous myocardial infarction or documented atherosclerotic disease were excluded, as were patients with diabetes, asthma or other medical condition known to affect autonomic function. Patients receiving tricyclic antidepressants were excluded. Some patients were receiving non-tricyclic psychotropic medications such as selective serotonin reuptake inhibitors (e.g. paroxetine) throughout the course of treatment, however these were the same both before and after treatment. All subjects underwent a Hamilton Rating Scale before and after treatment with ECT. The protocol for this study was approved by the institutional review board at the University of Iowa. All participants were studied in the Human Cardiovascular Physiology Laboratory of the Department of Cardiology, University of Iowa, Iowa City. After initial assessment by a research psychiatrist and administration of the Hamilton Depression Rating Scale, the subjects underwent a thirty minute pre-treatment assessment as follows: Respiration was measured using an inductance plethysmograph, and a continuous electrocardiogram was obtained using standard chest leads (Biotach and Pneumotrace, Gould Electronics, Valley View, OH). Electrocardiogram and respiration were recorded on an IBM 433DX / T computer. All subjects were breathing spontaneously and were not allowed to speak during the study. Measurement of heart rate variability was analyzed via power spectral analysis. Spectral analysis was restricted to the respiratory and RRI artifact-
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free segments (150–300 s). Analog-to-digital conversion was performed on-line at 1000 samples / s for the electrocardiogram and at 200 samples / s for respiration. The time series of the respiratory and RRI were viewed to be originated from non-equidistant sampled underlying signals, and a discrete Fourier transformation was applied for computing the resulting spectra using the CARSPAN 1.0 program (Mulder, 1992; Mulder et al., 1987; Robbe et al., 1987). Power spectral values in the HF band (0.15–0.40 Hz) determined the amplitude of respiratory sinus arrhythmia. We also determined the absolute power in the total spectrum (0.02–0.50 Hz). Because the physiological significance of the low frequency variability of RRI is controversial (Task Force, 1996), this paper will focus solely on the HF measures. The above measures were obtained initially after completion of Hamilton Ratings and preceding the first ECT. The measures were then obtained a second time after the subject had finished a course of sufficient duration as determined by the non-research clinical inpatient team as to either fully treat the depressive episode or to confer maximal benefit. The subjects were reassessed one day after completion of ECT with the power spectral analysis described above. The psychiatrist determining the Hamilton Depression Rating Scores before and after treatment was blind to the HRV measures and similarly the variability measures were obtained in a blinded fashion to the extent of depression severity. All patients received ECT on a schedule of three times per week with a constant current bidirectional square wave stimulus device (MECTA Model SR-1) (MECTA Corporation). The leads were placed bilaterally in the standard bifrontotemporal position. Stimuli were initiated using standard settings (1.0 ms pulse width, 40 Hz frequency and 1.0 s duration). Stimuli were titrated to seizure threshold at the first treatment. Seizure duration was between 30 and 40 s for the majority of treatments. Both motor convulsive movements using a cuff technique and electroencephalogram monitoring were used to assess seizure duration. Seizure duration exceeding 20 s was considered adequate. Subjects were administered the following agents intravenously: glycopyrrolate 0.2 mg, methohexital (0.75 mg / kg) and succinylcholine (0.6 mg / kg). The glycopyrrolate is an
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anticholinergic (antimuscarinic) agent used as a preanaesthetic to control secretions and optimize airway management during ECT. The duration of the anticholinergic effect is short (peaks within 30–45 min) and vagal blocking effects are of short duration (Ali-Melkila et al., 1993). Two of the nine subjects also received intravenous esmolol 30 mg, an ultrashort acting beta-blocker. Like the glycopyrrolate, esmolol was used for management of acute treatment effects. Esmolol has a half-life of only 9 min and would be expected to have no sustained cardiac effects following its elimination (Barbier et al., 1995). To avoid the confounding effects of these agents on parasympathetic measures, all subjects underwent the second HRV measures the following day (24–36 hours) following their last ECT. The data were not normally distributed and statistical analysis consisted of two-tailed Wilcoxon tests and Spearman correlation coefficients corrected for ties. Values are expressed as means6standard error of the mean. Significance was assumed at the p , 0.05 level.
Table 1 Depression ratings and subject characteristics Sex
Age
[ of treatments
Hamilton Score Pre-ECT
Hamilton Score Post-ECT
M F M F F M F F F
31 44 19 53 43 38 61 47 41
6 7 6 11 6 12 9 9 7
54 35 38 30 28 22 44 44 21
21 5 1 3 7 9 9 18 11
10206326 ms 2 to 2716159 ms 2 , p 5 0.008). This reduction in the amplitude of respiratory sinus arrhythmia contributed to the overall decrease in RR interval variability after ECT (from 26916892 ms 2 to 6756284 ms 2 p 5 0.03) (Fig. 1). Additionally, the magnitude of improvement in depressive symptoms as measured by the Hamilton Depression Rating Scale was positively correlated with the decrement in HF variability (Spearman rho 5 0.75, p 5 0.03) (Fig. 2).
3. Results The sample consisted of 9 patients diagnosed with major depressive disorder. In one case there was thought to be a possible comorbid diagnosis of schizophrenia, in another there was a history of alcohol abuse in remission. However, all patients met cross-sectional criteria for DSM-IV Major Depressive Episode. The mean age of the sample was 42.2612.2 years. The mean years of education was 12.463.3. The subjects had been hospitalized a mean of 4.262.7 previous times. All but one patient had had at least one previous episode of depression and the current episode had been present at least two weeks in all cases. Four of the subjects had undergone previous courses of ECT in the past. Please see Table 1 for more information on individual subjects. All patients were noted to have decrements in Hamilton Depression Rating Scales scores. The Hamilton Depression Rating Scale decreased from 3464 to 1162 ( p 5 0.008). RR interval tended to decrease after ECT (from 864645 ms to 770632 ms, p 5 0.17) and ECT markedly decreased the amplitude of respiratory sinus arrhythmia (from
4. Discussion In this study, we measured parasympathetic activity utilizing spectral analysis before and after ECT. Previous work has suggested that parasympathetic activity may be decreased in patients with major depression compared to non-depressed controls (Dalack and Roose, 1990; Rechlin, 1994; Rechlin et al., 1994c; Roose et al., 1991). Based on these findings, we hypothesized that treatment of depression with ECT would result in increased measures of parasympathetic tone compared to pre-treatment measures. In contrast to our proposed hypothesis, we found that treatment of depression with ECT was associated with a decrease in amplitude of the respiratory sinus arrhythmia, i.e. decreased parasympathetic activity. There are a number of reasons why this investigation differs from other studies which have assessed HRV in depression. Some previous studies have examined parasympathetic activity in a crosssectional manner comparing subjects with major
S.K. Schultz et al. / Journal of Affective Disorders 44 (1997) 13 – 20
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Fig. 1. The first graph depicts the change in the mean R-R interval (ms) before and after electroconvulsive therapy. The second demonstrates the change in the mean total power of the R-R interval (ms 2 ) and the third graph depicts the change in the high frequency power of the R-R interval (ms 2 ) before and after electroconvulsive therapy.
Fig. 2. The change in Hamilton Depression Rating Scores is shown in relationship to the change in high frequency power of the R-R interval (ms 2 ).
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depression to non-depressed controls or to patients with other diagnoses such as panic disorder (Yeragani et al., 1995, 1991). In the case of panic disorder, cross-sectional studies may be very useful, as panic disorder has been characterized as a state of chronically upregulated sympathetic activity, i.e. a trait-like phenomenon. Major depression is distinctly different by virtue of its episodic nature, so HRV measures may be dependent on the state of the depression at the specific time in which they are obtained. This may be the source for the variation in findings in HRV and depression studies. It is also possible that the use of ECT may have introduced an unanticipated confounding influence on parasympathetic activity. The transient autonomic effects of seizure induction involve an initial parasympathetic release followed by an increase in sympathetic activity, though these effects are confined to the time period immediately surrounding the treatment and post-ictal recovery phase (Gaines and Rees, 1992). For this reason we avoided the immediate recovery phase and obtained the follow-up measures on the day following the final treatment. However, it is possible that there could be some degree of sustained effects either from the seizure or the anesthetic medications used during the treatment that could persist more than 24 h following the last treatment, though this does not appear likely. In terms of neurotransmitter changes following ECT, studies examining CSF dopamine, serotonin and norepinephrine metabolites have not been successful in delineating a specific pattern or direction of change (Abrams and Essman, 1976; Jori et al., 1975; Nordin et al., 1971). It has also been noted that transient elevations in LH, FSH, GH and prolactin may occur, yet this does not have any known clinical significance (Skrabanek et al., 1981; Whalley et al., 1982). This study is clearly limited to addressing only the observed changes in parasympathetic tone in depressed patients following ECT. Because we did not examine a non-ECT treated depressed group for comparison or a non-depressed group receiving ECT, we are not able to make assertions regarding the relative influences of changes in depression per se versus the effects of ECT. Although the mechanism responsible for our observations is not known, this
study suggests that treatment of depression with ECT may be associated with cardiac vagal withdrawal (i.e. decreased parasympathetic activity) in some patients. A more thorough understanding of the autonomic effects of ECT may yield clinical useful insights. Particularly as ECT is often used in the treatment of elderly patients, a group at risk for cardiovascular disease, with the assumption that antidepressant medications may be more problematic in terms of cardiac side effects. If ECT is indeed associated with a decrement in parasympathetic tone, this may represent a risk factor for cardiac mortality particularly if applied to a group prone to cardiovascular illness (Singer et al., 1988). However, recent studies have shown that ECT may be used with relative safety even in populations with cardiovascular disease (Rice et al., 1994; Zielinski et al., 1993). Our study examined only subjects without known cardiovascular disease and did not assess outcome measures such as cardiac morbidity, so we cannot speak to this issue. Yet it is possible that a subgroup of cardiac patients may be vulnerable to increased morbidity in the face of a decrement in parasympathetic tone and would represent a group at particular risk for ECT complications. As ECT will continue to be used in persons with substantial medical comorbidity and with disproportionately greater frequency in persons over the age of 65 (Thompson et al., 1994), the pursuit of a better understanding of its autonomic effects seems a worthwhile endeavor. There is still an enormous amount of information to be learned about the mechanisms underlying the both efficacy and complications of ECT. Studies such as this may provide insights for larger controlled investigations.
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