- Email: [email protected]
Heart Rate Variability in Elderly Patients Before and After Electroconvulsive Therapy
Heart Rate Variability in Elderly Patients Before and After Electroconvulsive Therapy Eitan Nahshoni, M.D., M.Sc., Dov Aizenberg, M.D. Mayanit Sigler, M.D., Gil Zalsman, M.D. Boris Strasberg, M.D., Shula Imbar, B.Sc. Abraham Weizman, M.D.
Earlier studies have found major depression to be associated with increased cardiac mortality, hypothesized to result from reduced vagal modulation. Since reduced heart rate variability is part of normal aging, depression might predispose elderly patients to a higher risk. The authors investigated cardiac autonomic modulation, using spectral analysis, in 11 elderly depressed inpatients before and after electroconvulsive therapy (ECT). Cardiac vagal modulation increased significantly after ECT and was associated with symptom improvement, assessed by a significant decrease in the Hamilton Rating Scale for Depression. Further research is needed to elucidate the relationship between depression, autonomic modulation, and clinical risks in elderly patients. (Am J Geriatr Psychiatry 2001; 9:255–260)
H
eart rate variability (HRV) is the amount of fluctuation from the mean heart rate. Analysis of HRV provides prognostic information in several clinical settings. For example, in survivors of myocardial infarction, decreased HRV was found to be a strong and independent predictor of increased mortality.1 The proposed mechanism is reduced vagal modulation, which lowers the threshold for lethal arrhythmias. HRV is usually assessed with time-domain and frequency-domain techniques, which identify its coupling with respiration, baroreceptors, autonomic nervous system functioning, body temperature, metabolic rate, hormone levels, sleep cycles, etc.2,3 Time-domain analysis is perhaps the simplest to perform, providing measures such as the standard deviation (SD) of the interbeat in-
tervals, the square root of the mean squared differences of successive interbeat intervals, etc. Frequency-domain analysis, also called spectral analysis, provides the power spectrum of the heart rate. It reveals at least two frequency ranges in which the power accumulates— the low-frequency range (LF; [0.04–0.15 Hz]) and the high-frequency range (HF; [0.15–0.40 Hz]), which are modified by sympathetic and vagal traffic to the heart. Major depressive disorder (MDD) is accepted as a significant risk factor for increased mortality in patients after myocardial infarction, as well as for increased cardiovascular morbidity and mortality. The earliest observation, which supports the notion of higher cardiovascular mortality rates among institutionalized depressed patients, dates back to the study by Malzberg in 1937.4
Received November 19, 1999; revised August 2, 2000; accepted August 29, 2000. From the Psychogeriatrics Department and Research Unit, Geha Psychiatric Hospital, and the Institute of Cardiology, ICCU, Beilinson Hospital, Campus Beilinson, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address correspondence to Dr. Nahshoni, Geha Psychiatric Hospital, P.O.B 102, Petah Tikva 49100, ISRAEL. email: [email protected] Copyright 䉷 2001 American Association for Geriatric Psychiatry
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Heart Rate Variability and ECT Subsequent studies confirmed Malzberg’s original observation.5,6 Recently, Frasure-Smith et al.7 have demonstrated that depression while in the hospital after myocardial infarction is a significant predictor of increased cardiac mortality at 6 months. The impact of depression remained significant in a subsequent followup of their original cohort, from 6 to 18 months.8 Furthermore, Barefoot et al.9 have extended the follow-up period for up to 19.4 years and still found that cardiac patients who were depressed had a significantly heightened long-term risk. Carney et al.,10 who used 24-hour Holter monitoring, found that depressed patients with angiographically-documented coronary artery disease had significantly lower HRV than nondepressed coronary patients. Furthermore, epidemiological prospective studies have also demonstrated that depression increases the risk for fatal cardiac disease in communitydwelling adults.11,12 The demonstration that decreased HRV (decreased vagal modulation) is a significant risk factor for increased mortality in survivors of myocardial infarction led several research groups to hypothesize that MDD might be associated with reduced vagal modulation.13,14 Early time-domain analysis proved unfruitful in this area,13,15 although Balogh et al.16 correlated changes in short-term time-domain measures of HRV with clinical response to MDD treatment. Later, studies incorporating spectral analysis were confounded by the anticholinergic side effects of antidepressants (tricyclic drugs)17 or failed to correlate HRV measures to clinical improvement,18 although decreased cardiac vagal modulation was found in patients with MDD.19 Thus, different methodological designs and lack of standardized criteria for HRV measurement have made firm conclusions impossible. Recently, Schultz et al.20 reported on a relative decrease in cardiac vagal activity in nine depressed patients after ECT. Since the cardiac vagal decrement correlated with improvement of depressive symptoms, they suggested that treatment of depression with ECT might be associated with decreased cardiac vagal activity and concluded that it might be related to the resolution of depression and not the ECT per se. A different finding stems from a recent study reporting increased plasma norepinephrine in MDD, which might predispose patients to sustained ventricular arrhythmias and, as a consequence, to a high risk for sudden death.21 Thus, the mechanism of cardiac autonomic modulation in MDD, via analysis of HRV, is of more than purely academic interest.
256
The elderly depressed population is unique in the sense that physical illness and social factors might be posed as major determinants for increased morbidity and mortality. Several hypotheses have been proposed, such as comorbid physical fragility, the effects of depression leading to hypostatic pneumonia, raised cortisol levels, etc.22 However, Murphy et al.,23 who followed elderly depressed patients over 4 years, found that increased mortality rates are not due to poor physical health alone or to a single social factor. A plausible mechanism that depends on autonomic imbalance might be suggested, as follows: Since normal aging was found to be associated with reduced HRV, and depression was suggested to be associated with reduced HRV, depression in elderly patients might hamper their already-reduced HRV, thus exposing them to increased cardiac risk. Since most of the studies on HRV in depression thus far have been on young and middle-aged subjects, our working hypothesis was designed to assess whether ECT in elderly depressed patients is associated with a significant change in cardiac vagal modulation and whether such a change is associated with symptom improvement. We hypothesized that clinical response to ECT might correlate with increased cardiac vagal modulation. To this end, spectral analysis was performed in 11 physically healthy depressed inpatients before and after ECT, and various measures of HRV were calculated to assess the change in the sympatho-vagal imbalance. The Hamilton Rating Scale for Depression (Ham-D) was assessed concomitantly.
METHODS Study Population The study population included eight women and three men, age 60–84 years (mean 70Ⳳ7 years) with MDD, recurrent episode. All were interviewed by a senior psychiatrist (DA). The diagnosis of MDD was established according to DSM-IV criteria, following a structured interview using the guidelines of the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I/ P 2.0).24 Inclusion criteria were normal findings on physical examination and electrocardiography (ECG); routine blood tests on admission; and no history, signs, or symptoms of cardiovascular, pulmonary, neurological, or endocrine diseases. All patients had had at least two previous MDD episodes and were maintained on
Am J Geriatr Psychiatry 9:3, Summer 2001
Nahshoni et al. antidepressants before admission. The patients were subjected to ECT because of nonresponse to pharmacotherapy trials (some even showed deterioration on antidepressants) or because it was indicated by the urgency of the patient’s psychiatric status. Over the course of the study, all patients were on the same nontricyclic medication (either selective serotonin reuptake inhibitor [SSRI] or mianserin [Table 1]). The study population was neither on vasoactive or psychoactive (e.g., neuroleptic, anxiolytic) agents, nor were they smokers or alcohol consumers (Table 1). The study was approved by the Institutional Review Board of Geha Hospital. All patients provided written informed consent after receiving a complete description of the study. ECT The anesthetic medications administered were methohexital sodium (1.0 mg/dg) and succinylcholine (0.5 mg/kg), which were adjusted on the basis of the response after the first ECT treatment. The electrical dose was titrated to seizure threshold during the first treatment.25 Seizure presence and duration were confirmed by both clinical observation and electroencephalography (EEG) recordings. ECT was administered with a constant-current, brief bi-directional square-wave device (Thymatron DGx; Somatics Inc.). Right or left unilateral (d’Elia placement) ECT was used in all patients except one, who received bilateral (frontotemporal) ECT. Sessions were scheduled twice weekly for a maximum of 12, if needed. Heart Rate Recording and Analysis ECG recording was performed before onset of the ECT course and again upon its completion. To avoid the TABLE 1. Age, years 70 60 84 72 68 74 77 72 67 66 60
confounding effects of anesthetic agents on the HRV measures, the second recording was done 72 hours after the last treatment. The recordings were made in the same quiet room during spontaneous quiet breathing, after 10 minutes of adjustment in the supine position, between 10:00 A.M. and 12:00 A.M. (to avoid circadian rhythm bias). Subjects were studied at least 2 hours after a light breakfast and were told to refrain from consuming beverages containing caffeine in order to avoid the effects of diet and caffeine on sympathetic activity. One unfiltered ECG limb lead (LII) was digitized on-line with 16-bit signal resolution at 1,000 Hz, using a computerized system (Hipec analyzer HA-200/Aerotel Computerized Systems, Ramat Gan, Israel). A well-tested algorithm that uses a template and a threshold was chosen by the operator before recording to localize the fiducial point of every heartbeat during the recording. A series of 2,000 interbeat intervals was extracted in each recording session and stored for off-line analysis. All recordings and frequency-domain analyses were performed according to the recent standards published by the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.3 The nonparametric method used in our study is based on the fast-Fourier transform (FFT) algorithm and a Hanning spectral window. The following frequency bands were extracted from the power spectrum: total power (TP): 0.04 Hz–0.40 Hz, (to maintain comparability with other reports); low frequency (LF): 0.04 Hz–0.15 Hz; and high frequency (HF): 0.15 Hz–0.40 Hz. These indices are measured in units of power (ms2). We also calculated the LF norm [LF/TP) ⳯ 100] and the HF norm [HF/TP ⳯ 100], that is, the LF and HF powers in normalized units. This procedure, which emphasizes the controlled and balanced behavior of the two branches
Patients’ characteristics, including age, sex, medications and doses, pre-treatment Ham-D, and post-treatment Ham-D Sex
Medication
Dose, mg.
Pre-ECT Ham-D
Post-ECT Ham-D
F F F F M F F F M M F
Fluoxetine Fluvoxamine Fluvoxamine Paroxetine Paroxetine Fluvoxamine Mianserin Fluvoxamine Mianserin Mianserin Mianserin
40 250 250 40 30 300 45 250 45 45 60
22 27 20 26 34 20 23 21 22 29 24
7 20 13 9 7 18 5 4 3 19 23
Note: Ham-D⳱Hamilton Rating Scale for Depression; ECT⳱electroconvulsive therapy.
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Heart Rate Variability and ECT of the autonomic nervous system, also minimizes the between-measurement effects of variations in the TP on the values of LF and HF. We also calculated the LF/HF ratio, which provides a further assessment of the sympatho-vagal interplay. Clinical Rating The 17-item Hamilton Rating Scale for Depression (Ham-D)26 was used to assess symptom severity. The rating scales were obtained on the day of the first ECG recording (pre-ECT), and within 3 days after completion of the ECT course. Statistical Analysis We assessed comparisons between HRV measures and clinical ratings before and after ECT by means of two-tailed paired t-tests. A P value of ⬍0.05 was considered significant. All values are presented as meanⳲSD.
RESULTS The number of ECT sessions ranged from 6 to 12 (10.6Ⳳ2.2). A significant decrease in scores on the HamD was noted after ECT, from 24.36Ⳳ4.32 to 11.64Ⳳ7.23 (P⳱0.0001). TP showed no significant change after ECT (P⳱0.78), but there was a significant decrease in the LF norm; 71.24Ⳳ8.15 vs. 52.48Ⳳ17.38 (P⳱0.0058), as well as in the LF/HF ratio: 2.79Ⳳ1.28 vs. 1.44Ⳳ1.16 (P⳱0.018), and a significant increase in the HF norm, 28.78Ⳳ8.15 vs. 47.56Ⳳ17.35 (P⳱0.0057). There were no significant changes in LF and HF bands (in absolute units) after the ECT course.
DISCUSSION The relationship between cardiac autonomic modulation, as expressed by HRV measures and MDD might be crucial in elderly patients, in whom MDD could hamper their already age-related reduced cardiac autonomic modulation, exposing them to the risk of sudden death. Since experimental studies in animals and human subjects demonstrated that increased cardiac vagal modulation has protective effects against lethal arrhythmias,27 the present study was conducted to determine whether cardiac vagal modulation might increase after successful
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ECT treatment in elderly depressed patients. We found that successful treatment of depression with ECT was associated with an increase in cardiac vagal modulation. Some limitations of the study should be acknowledged. First are the limitations of the physiological correlates between the two branches of the autonomic nervous system and the spectral components of the heart rate. Namely, it is well accepted that vagal activity is a major contributor to the HF component.3 More controversial is the interpretation of the LF component, which is considered by some as a marker of sympathetic activity (especially, when expressed in normalized units),28 and by others as a parameter that includes both sympathetic and vagal modulations.3,29 These important limitations were demonstrated by Kingwell et al.,30 who compared direct measures of cardiac sympathetic activity and HRV at 0.1Hz, and later by Sloan et al.,31 who tried to correlate circulating catecholamines and the various spectral components. No significant correlation was found between the spectral estimates of cardiac sympathetic activity and circulating catecholamines. Taken together, the interpretation of the LF band as a robust measure of cardiac sympathetic activity is highly controversial. Consequently, the LF/HF ratio is considered by some investigators to mirror sympatho-vagal balance or to reflect sympathetic modulations. Despite this controversy, we tend to adopt the interpretation of Malliani et al.32 of the LF/HF ratio as a more useful index that reflects sympatho-vagal balance. Another limitation of our study might stem from the co-administration of antidepressants during the ECT treatment. For example, paroxetine, which has anticholinergic activity, might affect HRV measures. However, since Rechlin33 demonstrated that therapeutic doses of SSRIs (paroxetine and fluvoxamine) given to depressed patients did not change HRV measures after 14 days, we are less concerned with the effects of these drugs in our study on the measured cardiac autonomic activity. Furthermore, in an effort to minimize the effects of antidepressants on the HRV, the medications and doses were not changed before or during the ECT course. Previous studies examined cardiac autonomic imbalance in depression in a cross-sectional manner. Since depression is an episodic phenomenon, and firmly established normal standards of HRV measures with aging are not yet available, our study design sounds even more appropriate methodologically when each patient served as his or her own control.
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Nahshoni et al. We also attempted to control for organic causes that might interfere with modulation of the autonomic nervous system by selecting a physically healthy cohort and controlling for diet, smoking, and alcohol consumption. Diurnal variations in HRV measures were also minimized by performing the ECG recordings during the same time of day. The last ECG recording was chosen to be 72 hour after the last ECT treatment, in an effort to avoid the effects of the anesthetic medications and the seizure induction on autonomic activity.34 Recently, Schultz et al.20 reported on a decrease in vagal modulation after ECT in nine depressed patients. They found, contrary to our findings, that the decrease in cardiac vagal modulation correlated with clinical improvement. However, they assessed a younger cohort with comorbidity, whereas we assessed physically healthy MDD patients. Moreover, a different approach was used in the data analysis. Namely, their method of analysis was based solely on calculation of the HF band, which is claimed to correspond to vagal activity. But this issue is controversial, since the LF band, when patients are in the supine position, has also been reported to be mediated by vagal modulation.29 Hence, the use of only the HF band as a measure of vagal activity precludes a firm definitive conclusion concerning vagal activity after ECT. An earlier study, by Balogh et al.,16 correlated increased time-domain measures of HRV with clinical response to non-tricyclic antidepressant medications. Their study could be criticized on methodological grounds; namely, that the time-domain measures were calculated from 5 minutes of rhythm strips only, and, since time-domain measures depend on the length of the recording period, it is hard to compare these with results from other studies. However, their report of increased HRV with successful treatment of MDD conforms with our result of increased cardiac vagal modulation with successful MDD treatment. Our electrophysiological findings of a possible reduced cardiac vagal modulation before ECT and an increase in cardiac vagal activity after successful ECT may specifically indicate dysregulation of the autonomic nervous system in MDD. These results are complemented by a recent study reporting increased plasma norepinephrine levels in MDD patients.21 Such putative increased cardiac sympathetic activity is associated with increased risk for sustained ventricular arrhythmias and,
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as a consequence, with a high risk for sudden death. Recently, Rush et al.35 proposed vagus nerve stimulation (VNS) as a novel therapeutic intervention for treatment-resistant depression. The rationale for this intriguing study stems from recent clinical observations of mood improvement in patients treated by VMS for seizure disorders, the effects of VMS on metabolism and function of important limbic structures (depicted by positron-emission tomography), the role of anticonvulsants in mood disorders, and from animal and human studies in which VMS altered the concentrations of neurotransmitters (serotonin, norepinephrine, GABA, and glutamate), implicated in the pathogenesis of MDD. If MDD is associated with autonomic nervous system imbalance, depicted in our study as reduced cardiac vagal modulation, and depressed patients have abnormalities in brain regions that control the vagus nerve, then VNS might engage this dysfunctional circuit. Furthermore, one may hypothesize that HRV measures, which better depict cardiac vagal modulation, might serve as noninvasive biological markers in treatment- resistant depression. Inasmuch as VMS might improve resistant depression along the vagus–CNS axis, it might also confer protection from lethal arrhythmia down the vagus– heart axis. Therefore, an increase in cardiac vagal traffic to the heart might be speculated to reduce cardiac morbidity and mortality. Such speculations awaits largescale controlled studies. Although HRV declines with normal aging,36 quite interestingly, the increased cardiac vagal activity after ECT in our cohort of elderly patients suggests a detectable “spectral reserve” of autonomic modulation. Whether this increase in autonomic modulation might specify a subgroup of depressed patients; that is, those who are medication-resistant, is still an open question. In summary, our study is limited to addressing cardiac vagal modulation in physically healthy, elderly depressed patients before and after ECT. It would be of much clinical relevance to study the effects of ECT treatment on the autonomic activity of elderly patients with physical comorbidity, especially with physical diseases that are known to be associated with reduced HRV, for instance, diabetes mellitus. This warrants large-scale controlled studies, including a sham-ECT group, in elderly depressed patients with and without cardiac comorbidity.
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Heart Rate Variability and ECT
References 1. Bigger JT, Fleiss JL, Steinman RC, et al: Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992; 85:164–171 2. Appel ML, Berger RD, Saul P, et al: Beat-to-beat variability in cardiovascular variables: noise or music? J Am Coll Cardiol 1989; 14:1139–1148 3. 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. Eur Heart J 1996; 17:354–381 (published simultaneously in Circulation) 4. Malzberg B: Mortality among patients with involution melancholia. Am J Psychiatry 1937; 93:1231–1238 5. Black DW, Warrack G, Winokur G: The Iowa Record-Linkage Study, III: excess mortality among patients with “functional” disorders. Arch Gen Psychiatry 1985; 42:82–88 6. Murphy JM, Monson RR, Olivier DC, et al: Affective disorders and mortality. Arch Gen Psychiatry 1987; 44:473–480 7. Frasure-Smith N, Lesperance F, Talajic M: Depression following myocardial infarction: impact on 6-month survival. JAMA 1993; 270:1819–1825 8. Frasure-Smith N, Lesperance F, Talajic M: Depression and 18month prognosis after myocardial infarction. Circulation 1995; 91:999–1005 9. Barefoot JC, Helms MJ, Mark DB, et al: Depression and long-term mortality risk in patients with coronary artery disease. Am J Cardiol 1996; 78:613–617 10. Carney RM, Saunders RD, Freedland KE, et al: Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol 1995; 15:76:562–564 11. Anda R, Williamson D, Jones D, et al: Depressed affect, hopelessness, and the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993; 4:285–294 12. Pratt LA, Ford DE, Crum RM, et al: Depression, psychotropic medication, and risk of myocardial infarction: prospective data from the Baltimore ECA follow-up. Circulation 1996; 94:3123– 3129 13. Dalack GW, Roose SP: Perspectives on the relationship between cardiovascular disease and affective disorder. J Clin Psychiatry 1990; 51(suppl):4–9 14. Miyawaki E, Salzman C: Implications and potential uses of heart rate variability. Integrated Psychiatry 1991; 7:21–28 15. Yeragani VK, Pohl R, Balon R, et al: Heart rate variability in patients with major depression. Psychiatr Res 1991; 37:35–46 16. Balogh S, Fitzpatrick DF, Hendricks SE, et al: Increases in heart rate variability with successful treatment in patients with major depressive disorder. Psychopharmacol Bull 1993; 29:210–216 17. Yeragani VK, Pohl R, Ramesh C, et al: Effect of imipramine treatment on heart rate variability measures. Neuropsychobiology 1992; 26:27–32 18. Rechlin T, Weis M, Claus D: Heart rate variability in depressed patients and differential effects of paroxetine and amitriptyline on cardiovascular autonomic functions. Pharmacopsychiatry 1994; 27:124–128
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19. Rechlin T, Weis M, Spitzer A, et al: Are affective disorders associated with alterations of heart rate variability? J Affective Disord 1994; 32:271–275 20. Schultz SK, Anderson EA, van de Borne P: Heart rate variability before and after treatment with electroconvulsive therapy. J Affect Disord 1997; 44:13–20 21. Veith RC, Lewis N, Linares OA, et al: Sympathetic nervous system activity in major depression. Arch Gen Psychiatry 1994; 51:411– 422 22. O’Brien JT, Ames: Why do the depressed elderly die? Int J Geriatr Psychiatry 1994; 9:689–693 23. Murphy E, Smith R, Lindesay J, et al: Increased mortality rates in late-life depression. Br J Psychiatry 1988; 152:347–353 24. First MB, Spitzer RL, Gibbon M, et al: Structured Clinical Interview for Axis I DSM-IV Disorders: Patient Edition (SCID-I/P 2.0). New York, Biometrics Research Department, New York State Psychiatric Institute, 1996 25. Sackeim H, Decina P, Prohovnik I, et al: Seizure threshold in electroconvulsive therapy: effect of sex, age, electrode placement, and the number of treatments. Arch Gen Psychiatry 1987; 44:355–360 26. Hamilton M: Development of a rating scale for primary depressive illness. J Soc Clin Psych 1967; 6:278–296 27. Schwartz PJ, La Rovere MT, Vanoli E: Autonomic nervous system and sudden cardiac death. Circulation 1992; 85(suppl1):I-77–I91 28. Montano N, Gnecchi RT, Porta A, et al: Power-spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. Circulation 1994; 90:1826–1831 29. Pomeranz B, Macaulay RJB, Caudill MA, et al: Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985; 248:H151–H153 30. Kingwell BA, Thompson JM, Kaye DM, et al: Heart spectral analysis, cardiac norepinephrine spillover, and muscle sympathetic nerve activity during human sympathetic nervous activation and failure. Circulation 1994; 90:234–240 31. Sloan RP, Shapiro PA, Bagiella E, et al: Relationships between circulating catecholamines and low-frequency heart-period variability as indices of cardiac sympathetic activity during mental stress. Psychosom Med 1996; 58:25–31 32. Malliani A, Lombardi F, Pagani M: Power-spectrum analysis of heart rate variability: a tool to explore neural regulatory mechanisms. Br Heart J 1994; 71:1–2 33. Rechlin T: The effect of amitriptyline, doxepin, fluvoxamine, and paroxetine treatment on heart rate variability. J Clin Psychopharmacol 1994; 14:392–395 34. Gaines GY, Rees DI: Anesthetic considerations for electroconvulsive therapy. Southern Med J 1992; 85:469–482 35. Rush AJ, George MS, Sackeim HA, et al: Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry 2000; 47:276–286 36. Hisako T, Ferdinand J, Venditti JR, et al: Determinants of heart rate variability. J Am Coll Cardiol 1996; 28:1539–1546
Am J Geriatr Psychiatry 9:3, Summer 2001
Earlier studies have found major depression to be associated with increased cardiac mortality, hypothesized to result from reduced vagal modulation. Since reduced heart rate variability is part of normal aging, depression might predispose elderly patients to a higher risk. The authors investigated cardiac autonomic modulation, using spectral analysis, in 11 elderly depressed inpatients before and after electroconvulsive therapy (ECT). Cardiac vagal modulation increased significantly after ECT and was associated with symptom improvement, assessed by a significant decrease in the Hamilton Rating Scale for Depression. Further research is needed to elucidate the relationship between depression, autonomic modulation, and clinical risks in elderly patients. (Am J Geriatr Psychiatry 2001; 9:255–260)
H
eart rate variability (HRV) is the amount of fluctuation from the mean heart rate. Analysis of HRV provides prognostic information in several clinical settings. For example, in survivors of myocardial infarction, decreased HRV was found to be a strong and independent predictor of increased mortality.1 The proposed mechanism is reduced vagal modulation, which lowers the threshold for lethal arrhythmias. HRV is usually assessed with time-domain and frequency-domain techniques, which identify its coupling with respiration, baroreceptors, autonomic nervous system functioning, body temperature, metabolic rate, hormone levels, sleep cycles, etc.2,3 Time-domain analysis is perhaps the simplest to perform, providing measures such as the standard deviation (SD) of the interbeat in-
tervals, the square root of the mean squared differences of successive interbeat intervals, etc. Frequency-domain analysis, also called spectral analysis, provides the power spectrum of the heart rate. It reveals at least two frequency ranges in which the power accumulates— the low-frequency range (LF; [0.04–0.15 Hz]) and the high-frequency range (HF; [0.15–0.40 Hz]), which are modified by sympathetic and vagal traffic to the heart. Major depressive disorder (MDD) is accepted as a significant risk factor for increased mortality in patients after myocardial infarction, as well as for increased cardiovascular morbidity and mortality. The earliest observation, which supports the notion of higher cardiovascular mortality rates among institutionalized depressed patients, dates back to the study by Malzberg in 1937.4
Received November 19, 1999; revised August 2, 2000; accepted August 29, 2000. From the Psychogeriatrics Department and Research Unit, Geha Psychiatric Hospital, and the Institute of Cardiology, ICCU, Beilinson Hospital, Campus Beilinson, Petah Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address correspondence to Dr. Nahshoni, Geha Psychiatric Hospital, P.O.B 102, Petah Tikva 49100, ISRAEL. email: [email protected] Copyright 䉷 2001 American Association for Geriatric Psychiatry
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255
Heart Rate Variability and ECT Subsequent studies confirmed Malzberg’s original observation.5,6 Recently, Frasure-Smith et al.7 have demonstrated that depression while in the hospital after myocardial infarction is a significant predictor of increased cardiac mortality at 6 months. The impact of depression remained significant in a subsequent followup of their original cohort, from 6 to 18 months.8 Furthermore, Barefoot et al.9 have extended the follow-up period for up to 19.4 years and still found that cardiac patients who were depressed had a significantly heightened long-term risk. Carney et al.,10 who used 24-hour Holter monitoring, found that depressed patients with angiographically-documented coronary artery disease had significantly lower HRV than nondepressed coronary patients. Furthermore, epidemiological prospective studies have also demonstrated that depression increases the risk for fatal cardiac disease in communitydwelling adults.11,12 The demonstration that decreased HRV (decreased vagal modulation) is a significant risk factor for increased mortality in survivors of myocardial infarction led several research groups to hypothesize that MDD might be associated with reduced vagal modulation.13,14 Early time-domain analysis proved unfruitful in this area,13,15 although Balogh et al.16 correlated changes in short-term time-domain measures of HRV with clinical response to MDD treatment. Later, studies incorporating spectral analysis were confounded by the anticholinergic side effects of antidepressants (tricyclic drugs)17 or failed to correlate HRV measures to clinical improvement,18 although decreased cardiac vagal modulation was found in patients with MDD.19 Thus, different methodological designs and lack of standardized criteria for HRV measurement have made firm conclusions impossible. Recently, Schultz et al.20 reported on a relative decrease in cardiac vagal activity in nine depressed patients after ECT. Since the cardiac vagal decrement correlated with improvement of depressive symptoms, they suggested that treatment of depression with ECT might be associated with decreased cardiac vagal activity and concluded that it might be related to the resolution of depression and not the ECT per se. A different finding stems from a recent study reporting increased plasma norepinephrine in MDD, which might predispose patients to sustained ventricular arrhythmias and, as a consequence, to a high risk for sudden death.21 Thus, the mechanism of cardiac autonomic modulation in MDD, via analysis of HRV, is of more than purely academic interest.
256
The elderly depressed population is unique in the sense that physical illness and social factors might be posed as major determinants for increased morbidity and mortality. Several hypotheses have been proposed, such as comorbid physical fragility, the effects of depression leading to hypostatic pneumonia, raised cortisol levels, etc.22 However, Murphy et al.,23 who followed elderly depressed patients over 4 years, found that increased mortality rates are not due to poor physical health alone or to a single social factor. A plausible mechanism that depends on autonomic imbalance might be suggested, as follows: Since normal aging was found to be associated with reduced HRV, and depression was suggested to be associated with reduced HRV, depression in elderly patients might hamper their already-reduced HRV, thus exposing them to increased cardiac risk. Since most of the studies on HRV in depression thus far have been on young and middle-aged subjects, our working hypothesis was designed to assess whether ECT in elderly depressed patients is associated with a significant change in cardiac vagal modulation and whether such a change is associated with symptom improvement. We hypothesized that clinical response to ECT might correlate with increased cardiac vagal modulation. To this end, spectral analysis was performed in 11 physically healthy depressed inpatients before and after ECT, and various measures of HRV were calculated to assess the change in the sympatho-vagal imbalance. The Hamilton Rating Scale for Depression (Ham-D) was assessed concomitantly.
METHODS Study Population The study population included eight women and three men, age 60–84 years (mean 70Ⳳ7 years) with MDD, recurrent episode. All were interviewed by a senior psychiatrist (DA). The diagnosis of MDD was established according to DSM-IV criteria, following a structured interview using the guidelines of the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I/ P 2.0).24 Inclusion criteria were normal findings on physical examination and electrocardiography (ECG); routine blood tests on admission; and no history, signs, or symptoms of cardiovascular, pulmonary, neurological, or endocrine diseases. All patients had had at least two previous MDD episodes and were maintained on
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Nahshoni et al. antidepressants before admission. The patients were subjected to ECT because of nonresponse to pharmacotherapy trials (some even showed deterioration on antidepressants) or because it was indicated by the urgency of the patient’s psychiatric status. Over the course of the study, all patients were on the same nontricyclic medication (either selective serotonin reuptake inhibitor [SSRI] or mianserin [Table 1]). The study population was neither on vasoactive or psychoactive (e.g., neuroleptic, anxiolytic) agents, nor were they smokers or alcohol consumers (Table 1). The study was approved by the Institutional Review Board of Geha Hospital. All patients provided written informed consent after receiving a complete description of the study. ECT The anesthetic medications administered were methohexital sodium (1.0 mg/dg) and succinylcholine (0.5 mg/kg), which were adjusted on the basis of the response after the first ECT treatment. The electrical dose was titrated to seizure threshold during the first treatment.25 Seizure presence and duration were confirmed by both clinical observation and electroencephalography (EEG) recordings. ECT was administered with a constant-current, brief bi-directional square-wave device (Thymatron DGx; Somatics Inc.). Right or left unilateral (d’Elia placement) ECT was used in all patients except one, who received bilateral (frontotemporal) ECT. Sessions were scheduled twice weekly for a maximum of 12, if needed. Heart Rate Recording and Analysis ECG recording was performed before onset of the ECT course and again upon its completion. To avoid the TABLE 1. Age, years 70 60 84 72 68 74 77 72 67 66 60
confounding effects of anesthetic agents on the HRV measures, the second recording was done 72 hours after the last treatment. The recordings were made in the same quiet room during spontaneous quiet breathing, after 10 minutes of adjustment in the supine position, between 10:00 A.M. and 12:00 A.M. (to avoid circadian rhythm bias). Subjects were studied at least 2 hours after a light breakfast and were told to refrain from consuming beverages containing caffeine in order to avoid the effects of diet and caffeine on sympathetic activity. One unfiltered ECG limb lead (LII) was digitized on-line with 16-bit signal resolution at 1,000 Hz, using a computerized system (Hipec analyzer HA-200/Aerotel Computerized Systems, Ramat Gan, Israel). A well-tested algorithm that uses a template and a threshold was chosen by the operator before recording to localize the fiducial point of every heartbeat during the recording. A series of 2,000 interbeat intervals was extracted in each recording session and stored for off-line analysis. All recordings and frequency-domain analyses were performed according to the recent standards published by the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.3 The nonparametric method used in our study is based on the fast-Fourier transform (FFT) algorithm and a Hanning spectral window. The following frequency bands were extracted from the power spectrum: total power (TP): 0.04 Hz–0.40 Hz, (to maintain comparability with other reports); low frequency (LF): 0.04 Hz–0.15 Hz; and high frequency (HF): 0.15 Hz–0.40 Hz. These indices are measured in units of power (ms2). We also calculated the LF norm [LF/TP) ⳯ 100] and the HF norm [HF/TP ⳯ 100], that is, the LF and HF powers in normalized units. This procedure, which emphasizes the controlled and balanced behavior of the two branches
Patients’ characteristics, including age, sex, medications and doses, pre-treatment Ham-D, and post-treatment Ham-D Sex
Medication
Dose, mg.
Pre-ECT Ham-D
Post-ECT Ham-D
F F F F M F F F M M F
Fluoxetine Fluvoxamine Fluvoxamine Paroxetine Paroxetine Fluvoxamine Mianserin Fluvoxamine Mianserin Mianserin Mianserin
40 250 250 40 30 300 45 250 45 45 60
22 27 20 26 34 20 23 21 22 29 24
7 20 13 9 7 18 5 4 3 19 23
Note: Ham-D⳱Hamilton Rating Scale for Depression; ECT⳱electroconvulsive therapy.
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Heart Rate Variability and ECT of the autonomic nervous system, also minimizes the between-measurement effects of variations in the TP on the values of LF and HF. We also calculated the LF/HF ratio, which provides a further assessment of the sympatho-vagal interplay. Clinical Rating The 17-item Hamilton Rating Scale for Depression (Ham-D)26 was used to assess symptom severity. The rating scales were obtained on the day of the first ECG recording (pre-ECT), and within 3 days after completion of the ECT course. Statistical Analysis We assessed comparisons between HRV measures and clinical ratings before and after ECT by means of two-tailed paired t-tests. A P value of ⬍0.05 was considered significant. All values are presented as meanⳲSD.
RESULTS The number of ECT sessions ranged from 6 to 12 (10.6Ⳳ2.2). A significant decrease in scores on the HamD was noted after ECT, from 24.36Ⳳ4.32 to 11.64Ⳳ7.23 (P⳱0.0001). TP showed no significant change after ECT (P⳱0.78), but there was a significant decrease in the LF norm; 71.24Ⳳ8.15 vs. 52.48Ⳳ17.38 (P⳱0.0058), as well as in the LF/HF ratio: 2.79Ⳳ1.28 vs. 1.44Ⳳ1.16 (P⳱0.018), and a significant increase in the HF norm, 28.78Ⳳ8.15 vs. 47.56Ⳳ17.35 (P⳱0.0057). There were no significant changes in LF and HF bands (in absolute units) after the ECT course.
DISCUSSION The relationship between cardiac autonomic modulation, as expressed by HRV measures and MDD might be crucial in elderly patients, in whom MDD could hamper their already age-related reduced cardiac autonomic modulation, exposing them to the risk of sudden death. Since experimental studies in animals and human subjects demonstrated that increased cardiac vagal modulation has protective effects against lethal arrhythmias,27 the present study was conducted to determine whether cardiac vagal modulation might increase after successful
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ECT treatment in elderly depressed patients. We found that successful treatment of depression with ECT was associated with an increase in cardiac vagal modulation. Some limitations of the study should be acknowledged. First are the limitations of the physiological correlates between the two branches of the autonomic nervous system and the spectral components of the heart rate. Namely, it is well accepted that vagal activity is a major contributor to the HF component.3 More controversial is the interpretation of the LF component, which is considered by some as a marker of sympathetic activity (especially, when expressed in normalized units),28 and by others as a parameter that includes both sympathetic and vagal modulations.3,29 These important limitations were demonstrated by Kingwell et al.,30 who compared direct measures of cardiac sympathetic activity and HRV at 0.1Hz, and later by Sloan et al.,31 who tried to correlate circulating catecholamines and the various spectral components. No significant correlation was found between the spectral estimates of cardiac sympathetic activity and circulating catecholamines. Taken together, the interpretation of the LF band as a robust measure of cardiac sympathetic activity is highly controversial. Consequently, the LF/HF ratio is considered by some investigators to mirror sympatho-vagal balance or to reflect sympathetic modulations. Despite this controversy, we tend to adopt the interpretation of Malliani et al.32 of the LF/HF ratio as a more useful index that reflects sympatho-vagal balance. Another limitation of our study might stem from the co-administration of antidepressants during the ECT treatment. For example, paroxetine, which has anticholinergic activity, might affect HRV measures. However, since Rechlin33 demonstrated that therapeutic doses of SSRIs (paroxetine and fluvoxamine) given to depressed patients did not change HRV measures after 14 days, we are less concerned with the effects of these drugs in our study on the measured cardiac autonomic activity. Furthermore, in an effort to minimize the effects of antidepressants on the HRV, the medications and doses were not changed before or during the ECT course. Previous studies examined cardiac autonomic imbalance in depression in a cross-sectional manner. Since depression is an episodic phenomenon, and firmly established normal standards of HRV measures with aging are not yet available, our study design sounds even more appropriate methodologically when each patient served as his or her own control.
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Nahshoni et al. We also attempted to control for organic causes that might interfere with modulation of the autonomic nervous system by selecting a physically healthy cohort and controlling for diet, smoking, and alcohol consumption. Diurnal variations in HRV measures were also minimized by performing the ECG recordings during the same time of day. The last ECG recording was chosen to be 72 hour after the last ECT treatment, in an effort to avoid the effects of the anesthetic medications and the seizure induction on autonomic activity.34 Recently, Schultz et al.20 reported on a decrease in vagal modulation after ECT in nine depressed patients. They found, contrary to our findings, that the decrease in cardiac vagal modulation correlated with clinical improvement. However, they assessed a younger cohort with comorbidity, whereas we assessed physically healthy MDD patients. Moreover, a different approach was used in the data analysis. Namely, their method of analysis was based solely on calculation of the HF band, which is claimed to correspond to vagal activity. But this issue is controversial, since the LF band, when patients are in the supine position, has also been reported to be mediated by vagal modulation.29 Hence, the use of only the HF band as a measure of vagal activity precludes a firm definitive conclusion concerning vagal activity after ECT. An earlier study, by Balogh et al.,16 correlated increased time-domain measures of HRV with clinical response to non-tricyclic antidepressant medications. Their study could be criticized on methodological grounds; namely, that the time-domain measures were calculated from 5 minutes of rhythm strips only, and, since time-domain measures depend on the length of the recording period, it is hard to compare these with results from other studies. However, their report of increased HRV with successful treatment of MDD conforms with our result of increased cardiac vagal modulation with successful MDD treatment. Our electrophysiological findings of a possible reduced cardiac vagal modulation before ECT and an increase in cardiac vagal activity after successful ECT may specifically indicate dysregulation of the autonomic nervous system in MDD. These results are complemented by a recent study reporting increased plasma norepinephrine levels in MDD patients.21 Such putative increased cardiac sympathetic activity is associated with increased risk for sustained ventricular arrhythmias and,
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as a consequence, with a high risk for sudden death. Recently, Rush et al.35 proposed vagus nerve stimulation (VNS) as a novel therapeutic intervention for treatment-resistant depression. The rationale for this intriguing study stems from recent clinical observations of mood improvement in patients treated by VMS for seizure disorders, the effects of VMS on metabolism and function of important limbic structures (depicted by positron-emission tomography), the role of anticonvulsants in mood disorders, and from animal and human studies in which VMS altered the concentrations of neurotransmitters (serotonin, norepinephrine, GABA, and glutamate), implicated in the pathogenesis of MDD. If MDD is associated with autonomic nervous system imbalance, depicted in our study as reduced cardiac vagal modulation, and depressed patients have abnormalities in brain regions that control the vagus nerve, then VNS might engage this dysfunctional circuit. Furthermore, one may hypothesize that HRV measures, which better depict cardiac vagal modulation, might serve as noninvasive biological markers in treatment- resistant depression. Inasmuch as VMS might improve resistant depression along the vagus–CNS axis, it might also confer protection from lethal arrhythmia down the vagus– heart axis. Therefore, an increase in cardiac vagal traffic to the heart might be speculated to reduce cardiac morbidity and mortality. Such speculations awaits largescale controlled studies. Although HRV declines with normal aging,36 quite interestingly, the increased cardiac vagal activity after ECT in our cohort of elderly patients suggests a detectable “spectral reserve” of autonomic modulation. Whether this increase in autonomic modulation might specify a subgroup of depressed patients; that is, those who are medication-resistant, is still an open question. In summary, our study is limited to addressing cardiac vagal modulation in physically healthy, elderly depressed patients before and after ECT. It would be of much clinical relevance to study the effects of ECT treatment on the autonomic activity of elderly patients with physical comorbidity, especially with physical diseases that are known to be associated with reduced HRV, for instance, diabetes mellitus. This warrants large-scale controlled studies, including a sham-ECT group, in elderly depressed patients with and without cardiac comorbidity.
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