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Effect of sertraline on the recovery rate of cardiac
autonomic function in depressed patients after
acute myocardial infarction
Allan McFarlane, MD,a Markad V. Kamath, PhD,b Ernest L. Fallen, MD,b Victoria Malcolm, RN,b Finu Cherian,a
and Geoff Norman, PhDc Hamilton, Ontario, Canada
Background Brain serotonin is known to possess sympathoinhibitory properties. The aim of this clinical physiologic
study was to determine whether sertraline, a selective serotonin reuptake inhibitor, facilitates the rate of recovery of cardiac
autonomic function after an acute myocardial infarction (MI) in patients with depression.
Methods and Results Thirty-eight post–MI depressed patients were randomized to receive either sertraline 50
mg per day or placebo for 6 months. Depression was defined as a score >15 on the standardized Inventory to Diagnose
Depression questionnaire taken at prehospital discharge and again within 2 weeks of the acute infarct. Eleven stable post-
MI nondepressed patients served as a nonrandomized reference group during follow-up. Twenty-seven patients completed
the randomization. All 3 groups were followed up closely in a multidisciplinary post-MI clinic where they underwent serial
testing for both time and frequency domain heart rate variability (HRV) indices at baseline (1-2 weeks after MI) and at 6,
10, 14, 18, and 22 weeks. The rate of recovery of HRV was determined by use of a growth curve model based on
repeated-measures analysis of variance. There was a linear rate of increase in the SD of 24-hour N-N intervals (SDNN) in
the sertraline-treated group that paralleled that of the nondepressed reference group. This contrasted with a modest but sig-
nificant decline in SDNN in the placebo group from 2 to 22 weeks (t = 2.10, P < .05). However, the short-term power spec-
tral indices, while trending toward a more rapid rate of recovery in the treated group, did not reach statistical significance
compared with the placebo group.
Conclusion In depressed patients who have survived the acute phase of an MI sertraline facilitates the rate of recovery
of SDNN, a recognized predictor of clinical outcome. (Am Heart J 2001;142:617-23.)
Major and minor depressive disorders are common, depressant treatment has been fully elucidated.
with lifetime prevalence rates of 5% and 13%, respec- Although depressed patients may be vulnerable by tively.1 It is now recognized that depressed patients hav- virtue of occasional noncompliance in following pre- ing an acute myocardial infarction (MI) are particularly scribed treatment, it is highly unlikely that this factor predisposed to major adverse outcome within the first alone could explain the magnitude of the interaction.
year of the acute event.2,3 In a recent study Frasure- From a neurochemical perspective, depressed Smith et al reported an 18% and 27% incidence of major patients often have a chronically heightened sympa- and minor depression, respectively, in patients recover- thetic state.5 This has been attributed to putative mech- ing from an acute MI.4 Moreover, the hazards ratio for anism such as β-adrenoreceptor down-regulation and death within 6 months of the acute event was 5-fold abnormal 5-hydroxytryptamine (5-HT) receptor activity among a depressed compared with a nondepressed in the brain.5,6 It is now known that brain serotonin, a cohort. Although this association is a matter of growing neurotransmitter with central sympathoinhibitory prop- concern, neither the mechanisms nor the effect of anti- erties, is reduced in depression and could result in over-expression of sympathetic neural discharge.7 Heart rate variability (HRV) offers a unique noninva- From the Departments of aPsychiatry, bMedicine, and cClinical Epidemiology andBiostatistics, McMaster University Faculty of Health Sciences, Hamilton, Ontario, sive window through which to visualize the effects of centrally mediated changes in autonomic modulation of Supported by a peer-reviewed grant from the Heart and Stroke Foundation of cardiac function.8 It follows that by use of this technol- ogy it is possible to assess changes in cardiac sympatho- Submitted September 15, 2000; accepted April 26, 2001.
Reprint requests: Allan McFarlane, MD, McMaster University Medical Centre, modulation over time, using serial changes in HRV.
Room 3G 16, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. Interestingly, it is known that reduced HRV, one of the consequences of sympathoexcitation, is, as in depres- sion, an independent predictor of mortality within the first year of an acute MI.9 Moreover, several studies have 618 McFarlane et al
demonstrated a shift in sympathovagal balance toward a All 3 groups had baseline measurements of HRV 2 weeks heightened sympathetic state in patients with depres- after MI before sertraline or placebo was initiated. These sion.10-12 Our working model presumes that linkages included short-term supine and standing power spectral exist between the stress of an acute MI, either onset or indices of HRV under controlled laboratory conditions as well exacerbation of depression, cardiac autonomic imbal- as time domain statistics derived from 24-hour ambulatoryelectrocardiogram (ECG) Holter recordings. All 3 groups were ance, and adverse clinical outcomes. Several studies have then followed up by one nurse practitioner (V. M.) in a special demonstrated a gradual recovery of cardiac autonomic post-MI clinic (PMIC) at McMaster University Medical Centre function within 2 to 12 months after an acute MI.13,14 for 6 months. The PMIC is a multidisciplinary clinic with uni- Given that most serious outcome events occur within form standards of follow-up care for those discharged from the first 6 months of hospital discharge, it is reasonable our CCU, providing access to exercise rehabilitation, nutri- to assume that any intervention that rapidly returns auto- tional counseling, smoking cessation programs, and support- nomic balance in patients with persistent depressive ive psychotherapy. Hence all 3 groups received the same symptoms could stabilize the heart, thereby rendering it level of care throughout in the same clinic with the same less vulnerable to malignant ventricular arrhythmias. In caretaker(s). Each patient underwent identical 24-hour Holter this randomized, placebo-controlled clinical physiologic and laboratory testing at 2, 6, 10, 14, 18, and 22 weeks afterMI. IDD testing was repeated at 6, 10, 18, and 22 weeks. The study, we set out to determine the effect of sertraline, a research protocol was approved by the Institutional Review selective serotonin reuptake inhibitor (SSRI), on the rate Board of the Faculty of Health Sciences of McMaster Univer- of recovery of heart rate variability in depressed patients sity. All patients gave written informed consent.
The IDD is a self-completion instrument developed by Zim- merman et al.15 It covers all Diagnostic Statistical Manual’s crite- Between September 1996 and March 1999, 238 patients ria for major depressive disorder. It uses thresholds to determine admitted with an acute MI to our coronary care unit (CCU) the presence or absence of symptoms, each item being graded completed a standardized questionnaire designed to assess for severity as well as duration. The IDD is highly reliable with a depression. Eighty-six percent or 36% scored above a predeter- sensitivity of 81% to detect major depressive disorder. It corre- mined threshold that satisfied criteria for inclusion of both lates well with the Beck Depression Inventory (0.87), the Hamil- minor and major depression. Of these, 38 (44%) agreed to ton Rating Scale (0.80), and the Depression Interview Schedule enter a double-blind, randomized, placebo-controlled trial of (κ 0.9). The IDD is especially useful in measuring severity of sertraline 50 mg per day for 6 months. Eleven dropped out depressive symptoms with changes over time.16 after randomization within the first 2 months (6 in the sertra-line group and 5 in the placebo group), 3 because of drug side effects, 7 because of noncompliance, and 1 because of fre- For the time domain analysis, each 24-hour Holter tape was quent ventricular ectopy. Of the 27 patients who completed first annotated with an Oxford Medilog Excel scanner. A beat- the study, the average age was 62 ± 11 (SD) years and 16% or to-beat recognition software algorithm was assigned a configu- 59% were male. Eleven age-matched nondepressed post-MI ration class to each QRS complex. The normal sinus-conducted patients (9 male, age 62 ± 12 years) served as a nonrandomized N-N interbeat intervals were then downloaded for offline com- reference group to ascertain the “normal” rate of recovery of putational analysis. This included the average heart rate, the SD cardiac autonomic function in an otherwise nondepressed of all 24-hour N-N intervals (SDNN), and the root mean square cohort. Excluded were patients whose predischarge 24-hour of the SD of successive N-N intervals (rMSSD). The power Holter recordings showed either atrial fibrillation or ventricular spectrum of HRV was computed by autoregressive modeling.
ectopic beats greater than 100 per hour. Also excluded were This test was performed under carefully controlled laboratory patients with overt congestive heart failure, any life-threaten- conditions with a customized acquisition analog-to-digital sys- ing comorbid condition, an inability to complete the question- tem. A full description of our method can be found in a previ- naire, and those already on antidepressant medications.
ous report.17 In brief, the filtered ECG signal (2.2 minutes)was digitized with a 12-bit analog-to-digital converter at a sam- pling rate of 1 kHz. The instantaneous heart rate series was The design was a double-blind, randomized, placebo-con- resampled by linear interpolation to obtain an equally sampled trolled trial with stratification before randomization for those signal spaced 0.5 seconds apart. The power spectrum was on β-blocker therapy. Patients meeting the inclusion criteria for then computed from the HRV data of 256 samples. An autore- randomization had to score >15 on the Inventory to Diagnose gressive model of order number 14 was fitted to the HRV sig- Depression (IDD) questionnaire (vide infra) at least twice, once nal. Both the peak amplitude and the normalized area power just before hospital discharge and again 2 weeks later. This was contained in the low-frequency (LF) (0.05-0.15 Hz) and the to ensure stability in their mood alteration. The 38 patients high-frequency (HF) (0.15-0.40 Hz) bands were derived.
were then randomized to receive either sertraline 50 mg a day Because of anticipated low energies in signals from patients or a matched placebo tablet. There was, in addition, a third with poor left ventricular (LV) function, all patients were stud- group, a nondepressed nonrandomized reference group (n = ied in both the supine (20-30 minutes) and standing (10 min- 11) whose IDD score had to be less than 15.
utes) positions to maximize the signal-to-noise ratio in the LF American Heart JournalVolume 142, Number 4 McFarlane et al 619
Table I. Baseline demographics and clinical data
Sertraline Placebo
P
Parameter
IDD scores for sertraline-treated and placebo groups at base- line and at 22 weeks after MI. Asterisk, Significant drop in All values are expressed as mean with SD in parentheses. NS, Not significant at P =.05.
active treatment and placebo groups, respectively.
There were no significant group differences for risk fac-tors, cardiac medications, revascularization procedures, band as well as to assess, indirectly, a measure of baroreceptor thrombolysis, or history of previous MI. The IDD scores (range 16-43) averaged 21 ± 6.7 and 23 ± 6.4 for thesertraline and placebo group, respectively. It was only in the sertraline-treated group that a significant The primary outcome measurements were the time-depen- decrease in IDD scores (21 to 16, P < .05) was seen at dent changes in both time and frequency domain parameters of HRV. To estimate the rate of recovery of autonomic func- Similarly, there were no significant baseline differences tion, we used a growth curve model based on a repeated-mea- in any of the HRV measurements between the study sures analysis of variance (ANOVA).18 With this method the groups (Table II). There appeared to be a more robust data are fitted to a linear equation containing a polynomial HRV in the nondepressed reference group whose function of time, dummy variable for the sertraline versusplacebo group, and interactions. The functional form was reduced LF/HF ratio, slower heart rate, and higher rMSSDsuggest a comparatively higher vagal state. These baseline Y = b0 + b1 (X) + b2 t + b3 (t × X), differences, however, did not reach statistical signifi- where X is a dummy variable equal to 0 for the placebo group cance. On the other hand, there was a distinct difference and 1 for the sertraline group and t is elapsed time from initia- between the depressed patients and their nondepressed tion of treatment. Initial analysis also included quadratic and counterparts with respect to the ability to mount a cubic terms (and interactions), but these were not significant baroreceptor-mediated response to orthostatic stress (Fig- and were omitted from the reported analysis. Finally, a test of ure 2). Although only 1 nondepressed patient failed to significance was conducted by dividing each coefficient by its increase his LF power on standing erect, >50% (16/27) of SE. The analyses were conducted by use of a standard statisti- the depressed group actually exhibited an abnormal cal package (BMDPV, Los Angeles, Calif). All data are expressed decrease in LF power with orthostasis (P < .05).
as mean ± SEM. Baseline differences were analyzed by 1-way The most striking finding was an increase in SDNN in ANOVA and comparisons of the direction of orthostatic changesin LF power between the depressed and nondepressed refer- the sertraline-treated group in contrast to the steady ence group were computed using χ2 analysis. A value of P < .05 decline in SDNN in the placebo group (Figure 3 and Table III). During the 22 weeks after the acute infarction,the average SDNN for the sertraline group increased amodest 5% from 110.6 ± 10.1 milliseconds to 115.4 ± 11.0 seconds. Conversely, the depressed patients treated Baseline demographic and clinical characteristics with placebo showed a 9% decrease in SDNN. This dif- were similar between the sertraline and placebo groups ference in the trends of the sertraline versus placebo (Table I). Both groups had well-preserved LV function groups was confirmed by growth curve analysis where with ejection fractions averaging 53% and 58% for the the test of the group × time interaction was significant 620 McFarlane et al
Table II. HRV data at baseline
Parameter
Sertraline (n = 12)
Placebo (n = 15)
Reference (n = 11)
P value
Values are expressed as mean with SEM in parentheses. NS, Not significant at P = .05; nu, normalized units.
Comparison of the orthostatic responses of the LF power Growth curve plots of the rate of recovery of SDNN (in mil- between the depressed (n = 27) and nondepressed (n = 11) liseconds) conform to a linear model represented by the sertra- groups at baseline. Solid bars, Depressed group; open bars, line (dashed line), placebo (solid line), and nondepressed (dot- nondepressed group. Positive and negative refer to directional ted line) groups. Base on the abscissa refers to baseline (2 changes (increases or decreases respectively) of the LF power weeks after acute MI). The differences in rate of recovery from supine to standing states. There were significantly more between the sertraline-treated and placebo group are statisti- abnormal responses (ie, a fall in LF power on standing) in the cally significant (t = 2.10, P < .05).
depressed group (χ2 P < .05).
either of the depressed groups throughout the follow-up period (Table III).
(t = 2.10, P < .05). In all instances the same individual At the end of 6 months there was a 26% reduction in patients contributed to the mean values at every time IDD scores in the sertraline group (22.25 ± 2.0 to 16.5 period. During this same interval, it can be seen that the ± 1.5, P < .05) compared with no change in the nondepressed group showed a 28% increase in SDNN placebo group (23 ± 2.1 to 27 ± 8). However, there from 108 ± 8.6 to 138 ± 12 milliseconds.
was no significant correlation between the baseline Although no significant group differences were seen IDD scores and any of the HRV measurements. Neither in time trends for any of the remaining HRV parame- was there a correlation between changes in IDD scores ters (Table III) there were nevertheless 2 interesting over time and time-dependent changes in any HRV observations. First, in all 3 groups both time and fre- index. Although it was not the purpose of the study to quency domain HRV indices were not static but dis- measure clinical outcomes, the sample size being too played linear trends over time, indicating a progressive small, we note there were no deaths in any of the recovery toward normalization of autonomic balance.
groups during 6 months of follow-up, and the number Second, although sertraline did not appear to influence of patients requiring readmission for either unstable the rate of recovery of either the LF/HF ratio or the angina or reinfarction was too small to draw any statisti- resting supine LF power in the depressed groups, cal inferences. Of note, sertraline was well tolerated there was a persistent and significant reduction in LF with no adverse reactions or clinical symptoms among power indices in the nondepressed compared with American Heart JournalVolume 142, Number 4 McFarlane et al 621
Table III. Time course of HRV data
Weeks after MI
Parameter
Baseline
P value
NS, Nonsignificant between groups and with respect to rate of recovery.
*Statistically significant with respect to rate of recovery between sertraline and placebo groups.
†Significance only between nondepressed and both depressed groups.
Discussion
been shown that stimulation of central 5-HT1A recep- This study shows that, in depressed patients after tors can also lead to sympathoexcitation.23 acute MI, sertraline facilitates the rate of recovery of Autonomic regulation of cardiac function is usually SDNN, a potent predictor of cardiac mortality. For the expressed by noninvasive measurements of HRV. Both sertraline-treated group the trend toward restoring time and frequency domain indices of HRV are power- autonomic balance paralleled that of the nondepressed ful independent predictors of mortality within the first group. These rates of recovery were not dissimilar from year after MI.9,24 A relationship between depression those reported by Bigger et al13 and Lombardi et al.14 and HRV has also been well documented. Carney et al25 Conversely, the depressed group on placebo demon- reported that HRV, expressed as SDNN, was signifi- strated a modest but persistent decline in SDNN cantly lower in patients with coronary disease with throughout the 6 months of follow-up.
depression compared with nondepressed patients even Much has been written about the worrisome impact after correction for known covariates. Rechlin et al,10 of depression on adverse outcomes after MI.20 Post hoc using both time and frequency domain measures in analysis of data from several large clinical trials shows a patients with major depression, reported significantly strong correlation between psychosocial factors and lower values of SDNN and HF (vagal) power with little cardiac outcome events including sudden death.19,20 or no differences seen in a control group with reactive These and other studies support previous claims that depression confers a mortality risk as high as 4- to 6- Given these observations, one could make a case that fold within a year or so of an acute MI.21,22 Depression because antidepressants significantly improve HRV therefore emerges as a potent risk factor even after cor- parameters they should, at least theoretically, improve rection for known covariates such as LV dysfunction, clinical outcomes. Much depends on the cardiovascular previous MI, and ventricular arrhythmias.
effects of antidepressants generally and their influence A causal link is harder to unravel. In terms of physio- specifically on cardiac autonomic regulation. In con- logic mechanisms, it is now accepted that depression is trast to tricyclic antidepressants, which can cause associated with a heightened sympathetic state.5 This tachyarrhythmias, the SSRIs are well tolerated and pos- may be related to down-regulation of central postsynap- sess no anticholinergic effects and no effect on periph- tic β-adrenoreceptors or changes in activity of sero- eral autonomic tone such as postural hypotension, and tonin 5-HR2 receptors in the brain.6,23 With depression, they are not proarrhythmic. Balogh et al26 studied the chronic depletion of neurotransmitters such as sero- effects of antidepressants on SDNN and rMSSD in 17 tonin in central synaptic clefts could lead to interrup- patients with a major depressive disorder over 4 to 8 tion of inhibitory inputs to central sympathetic centers, weeks. Although they reported changes in SDNN that thereby increasing sympathetic neural discharge. It has correlated positively with improvement in depression 622 McFarlane et al
scores, especially with nontricyclics, the predrug HRV that sertraline had no effect on the chronotropic indices did not predict drug response nor was there response to exercise in patients on β-blocker therapy.
any correlation between HRV and depression scores, One of the major problems with drawing comparisons findings similar to our treatment group. Kharykin et al27 between studies that use different methods is the lack compared the effect of both doxepine and fluoxetine of a common gold standard, a problem particularly per- on 24-hour HRV measurements over 6 weeks. Using the tinent to both HRV measurements and instruments for Hamilton Depression Rating Scale they found that diagnosing depression. In this respect, measures of among the 10 of 14 patients responding to treatment HRV parameters in this report assiduously followed the there was a 17% increase in SDNN, whereas an actual guidelines recommended in the task force report of decrease in SDNN was seen in the nonresponders.
Although their population was noncardiac, our study In conclusion, our study shows that sertraline, a cen- showed similar findings in post-MI patients insofar as a tral serotonin reuptake inhibitor, facilitates the rate of significant increase in SDNN was observed in the sertra- recovery of HRV, an expression of cardiac autonomic line treatment in post-MI patients whereas an actual function, in depressed patients after an MI. The clinical decrease in SDNN occurred over time in the placebo relevance of these findings deserves comment. There is group. In an interesting study of patients with panic often a tendency to ascribe a critical physiologic role to disorder, Tucker et al28 observed a positive effect of flu- potent prognostic variables such as HRV as if iatrogenic oxetine on baroreceptor responsiveness as determined modification of the variable would necessarily have an by the LF power response to orthostasis. We saw a impact on prognosis. This may or may not be the case trend toward an increase in the orthostatic effect on LF because the variable may simply be a surrogate or power over time, but the differences between the ser- epiphenomenon rather than a direct precipitant of out- traline-treated and placebo groups did not reach statisti- come events. Given this caution, the results reported cal significance. Of interest, however, was the distinct here nonetheless help advance the notion that SSRIs impairment of the orthostatic (baroreceptor) response may play an important therapeutic role for susceptible in both depressed groups before randomization. These depressed patients recovering from an acute MI.
findings lend credence to the notion that early treat- Accordingly, they are worthy of being tested in larger ment of depression significantly improves HRV parame- ters, a known risk factor for adverse post-MI outcomes.
Potential limitations of this study deserve comment.
References
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