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Enhanced cardiovascular and catecholamine responses in women with depressive symptoms
International Journal of Psychophysiology 28 Ž1998. 157]166
Enhanced cardiovascular and catecholamine responses in women with depressive symptoms Kathleen C. LightU , Rupa V. Kothandapani, Michael T. Allen Departments of Psychiatry and Psychology, Uni®ersity of North Carolina, CBa7175, Medical Building A, Chapel Hill, NC 27599-7175, USA Di®ision of Education and Psychology, Uni®ersity of Southern Mississippi-Gulf Coast, 730 East Beach Boule®ard, Long Beach, MS 39560, USA Accepted 30 September 1997
Abstract To test the hypothesis that cardiovascular and sympathetic nervous system responses before and during behavioral stressors are exaggerated among subjects with depressed mood who do not have clinical depressive disorder. Sixty healthy women aged 18]49 were initially asked to complete the Beck Depression Inventory ŽBDI.. The 15 with the highest ŽDepressive Symptom group. and the 15 with the lowest BDI scores ŽControl group. underwent stress testing including baseline, postural challenge, a speech task describing responses to a recent anger-arousing experience and recovery. Both systolic and diastolic blood pressure levels were higher in the Depressive Symptom group during baseline, challenges and recovery. This group also showed shorter pre-ejection period Ža marker of enhanced cardiac sympathetic activation. and lesser heart rate variability across all test periods. During the speech task only, the Depressive Symptom group exhibited greater increases in plasma norepinephrine and higher cardiac output responses associated with decreased interbeat interval Žfaster heart rate.. These results support the a priori hypothesis regarding enhanced sympathetic and cardiovascular activity. Finally, the BDI scores correlated very highly with lack of perceived emotional social support, reinforcing prior research on the linkage between social isolation and severity of depressive symptoms. Q 1998 Elsevier Science B.V. Keywords: Depression; Sympathetic nervous system; Stress; Plasma norepinephrine; Cardiovascular system; Social support
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0167-8760r98r$19.00 Q 1998 Elsevier Science B.V. All rights reserved. PII S0167-8760Ž97.00093-7
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1. Introduction Depression is one of several psychological factors which have been shown to relate to increased risk of developing cardiovascular disease and to greater morbidity and mortality in patients with confirmed coronary heart disease ŽCHD. or myocardial infarction ŽMI. ŽCarney et al., 1988a, 1995a; Friedman and Booth-Kewley, 1987; Fielding, 1991.. Most recently, prospective research by Frasure-Smith and colleagues ŽFrasure-Smith et al., 1995; Lesperance et al., 1996. has shown that ´ both major depression and also depressed mood as indicated by a moderately increased score on the Beck Depression Inventory ŽBDI. were predictive of increased risk of subsequent mortality in patients tested while in hospital for recent myocardial infarction ŽMI.. Most of the deaths among patients with high BDI scores who did not meet criteria for major depression were observed to occur in patients who lacked emotional social support. Social isolation and lack of a confidant have been related to increased risk of cardiovascular death in numerous other investigations ŽOrth-Gomer and Unden, 1990; Williams et al., 1992; Berkman et al., 1992.. The study by Frasure-Smith et al. Ž1995. also indicated that the combination of a high score on the BDI when combined with more frequent premature ventricular complexes ŽPVCs. was associated with a tenfold increase in risk of early death. This observation was interpreted as consistent with the hypothesis that the high depressed mood in these patients might be accompanied by physiological changes including altered cardiac autonomic balance which might potentially trigger fatal arrhythmias or sudden cardiac death in patients with electrocardiographic evidence of increased vulnerability. Other research by Carney et al. Ž1988b, 1995b. documented that patients with CHD who meet criteria for major depression demonstrate significantly decreased heart rate ŽHR. variability on 24-h Holter monitoring. Decreased HR variability has been documented to be a powerful predictor of later cardiac death in patients with CHD and is interpreted by many investigators as evidence of altered cardiac autonomic balance ŽKleiger et al., 1987; Hayano et
al., 1991.. Recently, Krittayaphong et al. Ž1997. found that patients with confirmed CHD who showed high depression scores on the MMPI, but without clinical depression, demonstrated higher average HR levels and decreased HR variability over 24 h of Holter monitoring as well. A number of studies have confirmed that HR variability is altered as a function of differences in parasympathetic and sympathetic nerve activity to the myocardium ŽVybiral et al., 1989; Hayano et al., 1991; van den Meiracker et al., 1993.. Decreased HR variability may result from a change in the balance between the two autonomic systems modulating HR. An increase in cardiac sympathetic tone either with or without a concomitant decrease in parasympathetic tone can result in decreased HR variability due to increased sympathetic relative to parasympathetic drive ŽJennings and McKnight, 1994.. Although a faster or slower average HR level by itself is not a clear indicator of the autonomic mediation involved, decreased HR variability due to increased sympathetic relative to parasympathetic tone is normally associated with an increase in average HR level. Clinical depression in patients presumed free of CHD has been associated with a increase in 24-h mean HR levels ŽLahmeyer and Bellur, 1987. and enhanced adrenergic activity of this same patient group has been documented as exaggerated plasma norepinephrine ŽNE. responses to orthostatic challenge ŽRudorfer et al., 1985. and increased rate of NE release from sympathetic nerves Žindexed as NE appearance into an extravascular compartment. ŽVeith et al., 1994.. Although symptoms of depressed mood have been related to altered immune status, measures known to be sensitive to adrenergic activity ŽEvans et al., 1989., direct assessment of cardiovascular andror catecholamine responses to behavioral stressors in healthy individuals with depressed mood has been absent to date. Among cardiovascular measures sensitive to cardiac sympathetic activity Žbeta-1 receptor mediated increases in HR and contractile force., one of the best non-invasive indexes is the pre-ejection period ŽPEP.. Shortening of the PEP with increased HR level has been shown to result from increased efferent activity of the cardiac sympathetic nerves and infusion of
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isoproterenol, but not as a result of vagal blockade or atrial pacing ŽHarris et al., 1967; Binkley and Boudoulas, 1986.. PEP responses to behavioral challenges have been shown to characterize individuals who are high cardiac reactors to behavioral stress ŽSherwood et al., 1990. but has not been examined to date in relation to depressed mood. These findings led us to consider the following questions. First, is there the same association between depressed mood and reduced heart rate variability as well as other indicators of altered cardiovascular activity in healthy individuals free of CHD as in patients with such disease? Second, is depressed mood also associated with more definitive indexes of altered autonomic function, such as decreased PEP and increased plasma epinephrine ŽE. and NE response? Third, are these signs of autonomic alterations enhanced by exposure to psychological stress? Lastly, to what extent do these signs of altered peripheral sympathetic function relate similarly to lack of adequate social support? This investigation was intended to serve as an initial attempt to address these questions, using a sample of healthy young women aged 18]39 years. Women were selected for study because in such an initial investigation, it was desirable to reduce other potential sources of intersubject variability, such as gender, and because depression and depressed mood are reported to be more prevalent among women ŽLesperance et al., 1996.. ´ 2. Materials and methods 2.1. Subjects Sixty healthy women aged 18]49 were recruited to participate in a study of mood and stress response through local advertisements. Exclusionary criteria included: medical history of established hypertension; heart disease or other chronic illness; prior diagnosis of major or minor depressive disorder; current use of antidepressant or anti-anxiety medication; oral contraceptives; or any medication known to affect autonomic or cardiovascular activity. The protocol was ap-
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proved by our institutional review board and all women provided informed consent in writing before participating. All 60 subjects completed the Beck Depression Inventory ŽBDI., a 21-item instrument used to assess depressed mood. Subjects were paid $5 for completing screening procedures and the BDI. Then, the 15 women whose BDI scores fell into the top quartile Žrange 8]31, mean 16.7" 2.0. were classified as the Depressive Symptom group and the 15 subjects whose BDI scores were in the lowest quartile Žrange 0]4, mean 2.2" 0.3. were retained as the Control group. Each woman’s depressed mood status was not revealed to them at any point in the study, to avoid any confounding effects of labeling. The Depressive Symptom and Control women did not differ in age Ž32.5" 9.9 vs. 30.1" 9.0 years., height Ž64.8" 2.7 vs. 66.4 " 2.3 inches., weight Ž141.1 q26.5 vs. 142.2" 15.8 lbs., or ethnic group proportions Žtwo Black: 13 Whiterother vs. one Black: 14 Whiterother.. The 15 Depressive Symptom and 15 Control subjects subsequently underwent further testing, including further assessment of depression status using the Hamilton Depression Rating Scale, a scale which has been widely used for patient selection and assessment of treatment benefits in studies of clinical depression ŽWilliams, 1988.. To confirm that none of the Depressive Symptom subjects currently met criteria for clinical depression, the protocol dictated that any subject with a Hamilton Depression score of 15 or higher would undergo a clinical diagnostic interview; however, no subject exceeded a Hamilton score of 12 Žout of a maximum of 56.. No subject had a history of any psychiatric disorder; however, no additional screening for anxiety disorders or other clinical psychiatric disorder was performed. These subjects also completed a questionnaire on current emotional social support, the ‘appraisal support’ subscale of the Interpersonal Support Evaluation List ŽISEL. ŽCohen et al., 1985.. In our previous research, high appraisal social support indexed by this ISEL subscale was related to reduced clinic and ambulatory blood pressure ŽBP. levels in highly hostile men and women ŽBrownley et al., 1996..
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The Depressive Symptom and Control subjects also underwent a 90-min stress testing session as detailed below. They received an additional $25 for this testing. 2.2. Physiological recording procedures Auscultatory BP levels were determined using a custom designed and built automated cuff inflationrdeflation system attached to a standard inflatable arm cuff positioned around the subject’s left arm. Cuff pressure and Korotkoff sounds obtained using a piezoelectric microphone over the brachial artery under the lower edge of the cuff were recorded as analog signals using the Videograph II computer-based chart recorder system. Systolic ŽSBP. and Diastolic ŽDBP. levels were defined as the pressure at the onset ŽPhase 1. and disappearance ŽPhase 5. of Korotkoff sounds. A series of three to five BP readings were recorded immediately after instrumentation with an additional signal corresponding to onset and disappearance of Korotkoff sounds as heard through a stethoscope by a trained assistant; these were used to standardize subsequent scoring to match the stethoscopic determinations. Impedance cardiography was utilized for noninvasive estimation of stroke volume ŽSV.. A Minnesota Impedance Cardiogaph ŽModel 304B. was used in conjunction with a tetrapolar band electrode configuration ŽCleartrace No. 1700. with two bands encircling the upper and lower neck and two located around the thorax. Impedance and electrocardiogram ŽECG. signals Žobtained by means of external chest electrodes. were processed on-line and subsequently edited for accuracy using the Cardiac Output Program ŽCOP, Microtronics Inc.. software which was developed and validated in our laboratory. For each minute of interest, a 40-s continuous sample of waveforms was processed to generate an ensemble-averaged cardiac cycle. This ensemble average was used to quantify the PEP, an index of cardiac sympathetic activity ŽHarris et al., 1967., SV Ždetermined via the Kubicek equation. and heart rate ŽHR.. SV and HR were used to derive cardiac output ŽCO. and when combined with concurrently obtained mean arterial BP, to calculate
total peripheral resistance using standard formulas Žfor details see Sherwood et al., 1990.. Heart rate variability during the baseline and task periods was derived from the 40-s continuous ECG data obtained and processed by the COP software. Interbeat intervals ŽIBIs. were first calculated from COP data and, from these, the ‘mean successive difference’ ŽMSD. was calculated for each sample based on the average of the differences between each interbeat interval and the one which followed it. Hayano et al. Ž1991. have confirmed through direct manipulation of vagal and sympathetic input that the MSD statistic is highly sensitive to alterations in autonomic balance and as strong or stronger than frequency domain measures obtained via spectral analysis in indexing changes in cardiac sympathetic and vagal tone. 2.3. Experimental protocol After instrumentation and stethoscopic readings Ž20]25 min., the subject continued to rest quietly in a seated position for a baseline period of 21 min. Following the baseline rest, the subject went through the Postural Challenge, rising from sitting to standing for 3 min. After being reseated for 5 min and a second 5-min instruction period, subjects underwent the Speech task, where she was asked to talk for 3 min about a recent personal incident that had made her angry. A preparatory period of 2 min preceded the speech. Following the speech, subject rested and recovered for 11 min. Cardiovascular responses were obtained every other min Žmin 1, 3, 5, etc.. during each of these events. Blood samples were drawn at the end of the baseline period and after each of the two stressors to assess plasma E and NE responses. 2.4. Plasma catecholamine assays Blood was drawn into EDTA tubes kept on ice and centrifuged to separate plasma within a few minutes after collection. Plasma was pipetted into tubes, rapidly frozen and maintained at y 608C until assayed. The assay procedure involved extraction of catecholamines from 1.0 ml of plasma
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with activated lumina, injection of the acid extract onto a reverse phase C-18 column and separation with a mobile phase of 2.6% acetonitrile and a 0.2-g sodium octane sulfonate in phosphaterEDTA buffer pumped at 1 mlrmin and 1600 psi ŽLC 10AD Pump, Shimadzu Corp, Kyoto, Japan.. The E and NE levels were detected with an ESA Coulochem Electrochemical Detector ŽESA, Bedford, MA, USA., recorded using the PE-Nelson Analytical System and analyzed with PE-Nelson Turbochrome Software ŽCupertino, CA, USA.. The lower limit of quantification with this system was 5 pgrml and intra- and inter-assay coefficients of variation were less than 10%. 2.5. Data analyses Cardiovascular data were averaged during the conclusion Žmin 17, 19 and 21. of the baseline period, during minute 1 and 3 of each of the two challenges and during the recovery period Žmin 1, 3, 5, 7, 9 and 11.. For each cardiovascular measure ŽSBP, DBP, PEP, CO, TPR, IBI and MSD., a separate repeated measures analysis of variance ŽANOVA. was performed using a two ŽGroup: Depressed vs. Control. by four ŽTime Periods: Baseline vs. Posture vs. Speech Challenge vs. Recovery. design. For SV, CO, TPR, SBP, DBP and MSD, these analyses were performed with body surface area ŽBSA. as a covariate. Indexing for BSA is recommended for SV, CO and TPR measures; also, increased BSA has been associated with increased BP in other studies and this same relationship was seen in the present sample Ž P0.007.. Increased BSA was also found to be related to decreased MSD in this sample Ž P0.025.. When the Group= Time Periods effect was significant or approached significance using the more conservative MANOVA solution, subsequent least square means comparisons during each individual time period were used to determine whether groups differed only during the stressors. Plasma E and NE levels were compared at baseline between Groups by means of t-tests and results during each task were individually examined as percent increases from baseline. These analyses involved reduced degrees of freedom since inability to obtain an adequate blood
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sample or technical problems with the assay led to having complete catecholamine data in only 10 Depressed Mood and nine Control subjects. Lastly, the relationship of social support to depressed mood was assessed using Pearson correlation coefficients, to determine whether effects of depressed mood and social isolation may be substantially overlapping. 3. Results 3.1. Cardio®ascular responses The Depressive Symptom group was found to have higher blood pressure levels than the Control group both at rest and during the two stressors. Repeated measures ANCOVAs yielded a significant main effect of Group for SBP and DBP Ž F1,27 s 4.62 and 4.81, P- 0.05; see Figs. 1 and 2.. Both groups showed approximately equivalent increases in SBP and DBP to the two stressors and as a result the Group= Time Periods interactions for these variables were non-significant Ž P) 0.20.. The subjects with Depressive Symptoms also demonstrated consistently shorter PEP and reduced heart rate variability assessed by MSD across rest and stressor periods compared with control subjects ŽMain effect of Group, F1,28 s 4.21 and F1,27 s 4.27, P- 0.05., suggesting a general increase in cardiac sympathetic tone relative to parasympathetic tone. As with the BP measures, for PEP and MSD analyses, the interaction with Time Periods was non-significant, indicating no further enhancement of group differences during stress Žsee Figs. 3 and 4.. For CO and TPR analyses, the main effect of Groups was non-significant Ž P) 0.20.. For CO, however, the Group= Time Periods interaction was only marginally significant Ž P- 0.068.. Nevertheless, based on a priori hypotheses, subsequent comparisons were made separately at each time period. These comparisons indicated no group differences during Baseline, Posture Challenge or Recovery Ž P) 0.30., but during the Speech task, the Depressive Symptom subjects had higher CO than the control subjects Ž F1,27 s 4.72, P- 0.05; see Fig. 5.. This group difference selectively during the Speech task was due to an
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Fig. 1. Systolic blood pressure ŽSBP. levels adjusted for body surface area in the Depressive Symptom group are significantly higher than in the Control group across all task periods Ž P- 0.05..
increase in CO from baseline to speech among the Depressed group Žfrom 7.45 to 7.94 lrmin, P- 0.05. while the Control group showed essentially no change in CO during speech Žfrom 6.88 to 6.70 lrmin, Ps ns.. To determine whether these group differences in CO responses to the Speech task were due to increased HR or SV among the Depressive Symptom group Žthe two physiological determinants of CO., results of group comparisons of IBI Žthe inverse of HR. and SV were examined. SV responses of the two groups did not differ across any of the time periods Ž P) 0.30.. For IBI, there was a strong trend toward shorter IBI Žfaster HR. in the Depressive Symptom group across all time periods Ž F1,28 s 3.72, P- 0.064.. Like the results for CO, for IBI, group differences were evident only during the Speech task Ž F1,28 s 4.62, P- 0.05., indicating
Fig. 2. Diastolic blood pressure ŽDBP. levels adjusted for body surface area in the Depressive Symptom group are significantly higher than in the Control group across all task periods Ž P- 0.05..
Fig. 3. Pre-ejection period ŽPEP. levels in the Depressive Symptom group are significantly decreased compared with the Control group across all task periods Ž P - 0.05..
that higher HR during the Speech task contributed to the increased CO responses of the Depressive Symptom group Žsee Fig. 6.. 3.2. Plasma catecholamine responses Baseline levels of plasma E and NE did not differ reliably between the Depressive Symptom and Control groups Ž44.8 vs. 36.3 and 225 vs. 211 ngrml, P) 0.40.. For subsequent analyses involving percent changes in NE from baseline levels, a significant main effect of Groups and a significant Group= Time Periods interaction were obtained Ž F1,17 s 4.17, P- 0.05 and 6.65, P- 0.02.. The Depressive Symptom subjects showed greater increases in plasma NE to the Speech task Žq59.9% vs.q15.5%, P- 0.012. and a trend toward greater increase in NE to the Posture Challenge Žq37.7% vs.q19.7%, P) 0.10. Žsee Fig. 7.. For plasma E
Fig. 4. Heart rate ŽHR. variability levels indexed by the mean successive difference ŽMSD. in the Depressive Symptom group are significantly decreased compared with the Control group across all task periods Ž P - 0.05..
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Fig. 5. Cardiac output responses adjusted for body surface area in the Depressive Symptom group are greater than in the Control group during the Speech task Ž P- 0.05. but not during the Postural Challenge ŽStand..
responses to stressors, the direction of response to the Speech task differed between the two groups, with Depressed subjects showing an increase and Control subjects showing a decrease from baseline, but this difference in plasma E response was non-significant Žq5.2% vs.y8.6%, P) 0.10.. Neither group showed an increase in plasma E in response to the Postural Challenge Ž0% vs.y13.2%, P) 0.10.. These results are consistent with the cardiovascular findings in indicating an increase in sympathetic nervous system activity in the subjects with Depressive Symptoms. 3.3. Relationship of low social support to se®erity of depressi®e symptoms To address the hypothesis that high scores on scales of depressive symptoms like the BDI may
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Fig. 7. Percent increase from baseline in plasma norepinephrine ŽNE. levels in the Depressive Symptom group is greater than in the Control group during the Speech task Ž P - 0.012. but not during the Postural Challenge ŽStand..
be related to lack of emotional social support, correlational analyses were performed to determine the association of ISEL appraisal support scores with BDI. Although we had hypothesized that depressive symptoms would be associated with low support, the strength of the inverse relationship between appraisal support and depression severity in this sample of healthy young women was greater than anticipated Ž r 29 s y0.82, P- 0.0001.. Thus, although our a priori hypotheses were directed at examining the relationship of depressive symptoms to altered cardiovascular responses, the extensive overlap of these symptoms with low support suggests that had we grouped our subjects on the basis of low vs. high social support from a confidante, our observed group differences would have been substantially the same. 4. Discussion
Fig. 6. Interbeat interval in the Depressive Symptom group is shorter Žindicating faster heart rate. than in the Control group during the Speech task Ž P- 0.05. but not during the Postural Challenge ŽStand..
In this sample of healthy young women, the presence of a subclinical depressive state as indicated by high scores on the Beck Depression Inventory was associated with several signs of enhanced peripheral sympathetic activity. The most definitive evidence was derived from plasma catecholamine responses to the stressors. The women with depressive symptoms demonstrated greater percent increases in plasma NE levels than women with few or no dysphoric symptoms in response to the stress of a simulated speech on
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a recent anger-arousing experience. They also showed directional trends toward higher plasma NE reactivity to the postural challenge and in plasma E reactivity to both tasks, although these were non-significant with the present small sample size and high inter-individual variability which is typical of these measures. Although baseline levels of plasma NE and E did not differ between the depressed and control subjects, there was other evidence of a generalized increase in sympathetic activity to the heart which was evident during both rest and stress. First, the women reporting depressive symptoms had increased SBP and DBP and shorter PEP levels both at rest and during stress. Decreased PEP is associated with increased sympathetic drive on the myocardium ŽHarris et al., 1967; Binkley and Boudoulas, 1986.. Although there is no ‘pure’ index of increased centrally mediated efferent sympathetic nerve activity to the heart which can be obtained non-invasively, PEP is widely viewed as one of the better indirect indexes of such activity. The magnitude of difference between the PEP levels of the women with vs. without depressive symptoms was in fact very similar to the differences in PEP observed before vs. after beta-blockade with propranolol in a prior study in our laboratory ŽGirdler et al., 1993.. Furthermore, this interpretation of augmented adrenergic drive on the heart is strengthened by the findings of decreased HR variability as assessed by the MSD comparisons. Since the depressed group showed reduced HR variability, this suggests an alteration of the balance between sympathetic and parasympathetic tone influencing HR. When decreased HR variability is present together with an increase in HR level, as reflected by the decreased MSD together with the shorter mean IBI observed in these women with subclinical depressive symptoms, the most plausible explanation for this decrease in HR variability is an enhancement of cardiac sympathetic activity relative to vagal tone. The sum of the evidence from the plasma NE and increased HR and CO during the speech stressor and the generalized decrease in HR variability and shortened PEP in these healthy young women with subclinical depression indicates an increase on tonic sympathetic activity to the heart
and an increase in sympathetic responsivity to behavioral stress. These effects are similar to the observations of increases in both tonic and reactive NE measures in patients with major clinical depression ŽRudorfer et al., 1985; Veith et al., 1994.. They also document the similarity of healthy young adults with subclinical depression and older CHD patients with depression or depressed mood in regard to increased mean HR with decreased HR variability ŽCarney et al., 1988b, 1995b; Krittayaphong et al., 1997.. Thus, the alterations in adrenergic function associated with subclinical depression appear to be independent of the effects of the advanced cardiovascular alterations seen in the CHD patients; it is a primary rather than a secondary physiological dysregulation. Nevertheless, it is obvious that symptoms of depression may be magnified by the stress of CHD or any chronic illness and may be directly precipitated in vulnerable individuals by a sudden worsening of symptoms and prognosis such as after an acute MI ŽLesperance et al., 1996.. ´ These interpretations must be qualified by two study limitations. First, although the Hamilton was used to screen for clinical depression, no full psychiatric screening was performed to rule out the possibility that some subjects might have met criteria for anxiety disorders or other clinical psychiatric disorders. Second, both the modest sample size and the restriction of the sample to young women indicates a need for further examination of these relationships in a larger and more diverse sample. The finding that these young women with depressive symptoms had higher blood pressure than control women at rest as well as during acute stressors indicates that homeostatic mechanisms regulating blood pressure may have undergone a chronic resetting, allowing blood pressure to be maintained at a higher set-point. Further increments of this kind could potentially lead to sustained hypertension. It is also clear that these kinds of alterations in peripheral sympathetic activity can enhance risk of developing hypertension-related morbidity ŽSimonsick et al., 1995. and both coronary ischemia and arrhythmia ŽCarney et al., 1995a; Cameron, 1996.. Increased efferent sympathetic drive on the myocardium may
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alter ventricular fibrillation threshold in vulnerable patients, which may help explain the tenfold increase in mortality observed by Frasure-Smith et al. Ž1995. in post-MI patients with both high BDI scores and a high rate of PVCs. Increased plasma NE and high HR may increase the likelihood of vasospasm in damaged and partially occluded coronary arteries, thus leading to an increasing risk of myocardial ischemia possibly leading to angina or even MI due to both increased myocardial demand and diminished supply ŽKrittayaphong et al., 1997.. The present results and those of Sheffield et al. Ž1998. in patients with CHD suggest that there may be an increased impact of life stressors in CHD patients with depressive symptoms as well. Mental stress has been found to be a potent trigger for cardiac events in patients with documented CHD, presumably in part through surges in sympathetic activity ŽBrackett and Powell, 1988; Krantz et al., 1994; Mittleman et al., 1995.. The connection between severity of depressive symptoms and lack of adequate social support was also reinforced by the present findings. In these healthy young women, there was a very strong inverse correlation between the magnitude of perceived emotional Žconfidante. support and depressive symptoms. Previous investigations have shown associations between low social support and cardiovascular morbidity which are strikingly similar to observed associations between depression and the same morbid health outcomes ŽOrth-Gomer and Unden, 1990; Berkman et al., 1992; Williams et al., 1992.. Since social isolation can promote dysphoric mood and conversely feeling sad and losing interest in usual activities Žthe two central components of depression. may tend to reduce the frequency of contacts with supportive friends and relatives, it may not be possible to fully separate the effects of these two psychosocial factors. Our research group and others ŽOrth-Gomer and Unden, 1990; Brownley et al., 1996. have found that adequate social support may reduce the cardiovascular changes associated with long-term stress of a hostile or Type A behavior pattern, and other studies ŽKamarck et al., 1990; Lepore et al., 1993. have shown the benefits of immediately available support on acute
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cardiovascular responses to lab stressors. Further study of depression and depressed mood must most appropriately also focus on social support measures and vice versa. 5. Summary In summary, among healthy young women who had no current or prior history of clinical depression, the presence of depressive symptoms Žsubclinical depression. was related to increased blood pressure, evidence of increased adrenergic drive on the heart both at rest and during behavioral stressors and an increase in cardiac output and plasma norepinephrine responses to a speech about a recent anger-arousing experience. These results indicate that peripheral adrenergic dysregulation, previously reported in clinical depression, is detectable in subjects with much milder dysphoric symptoms. The findings also add to observations on the potential physiological mechanisms which may contribute to the documented increase in morbidity and mortality in patients with coronary heart disease who have clinical depression or milder depressive symptoms. Lastly, these subjects demonstrated a direct correspondence between the severity of reported depressive symptoms and the lack of emotional social support, extending prior research on the linkage between these two psychosocial factors. References Berkman, L.F., Leo-Summers, L., Horwitz, R.I., 1992. Emotional support and survival after myocardial infarction: a prospective population-based study of the elderly. Ann. Intern. Med. 117, 1003]1009. Binkley, P.F., Boudoulas, H., 1986. Measurement of myocardial inotropy. In: Leier C.V. ŽEd.., Cardiotonic Drugs: A Clinical Survey. Marcel Dekker, New York, pp. 5]48. Brackett, C.D., Powell, L.H., 1988. Psychosocial and physiological predictors of sudden cardiac death after healing of acute myocardial infarction. Am. J. Cardiol. 61, 979]983. Brownley, K.A., Light, K.C., Anderson, N.B., 1996. Social support and hostility interact to influence clinic, work and home blood pressure in Black and White men and women. Psychophysiology 33, 434]445. Cameron, O., 1996. Depression increases post-MI mortality: How? ŽEditorial comment.. Psychsom. Med. 58, 111]112. Carney, R.M., Freedland, K.E., Rich, M.W., Jaffe, A.S., 1995a. Depression as a risk factor for cardiac events in established
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coronary heart disease: a review of possible mechanisms. Ann. Behav. Med. 17, 142]149. Carney, R.M., Saunders, R.D., Freedland, K.E., Stein, P., Rich, M.W., Jaffe, A.S., 1995b. Association of depression with reduced heart rate variability in patients with coronary heart disease. Am. J. Cardiol. 76, 562]564. Carney, R.M., Rich, M.W., Freedland, K.E., Saini, J., TeVelde, A., Simeone, C., Clark, K., 1988a. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom. Med. 50, 627]633. Carney, R.M., Rich, M.W., TeVelde, A., Saini, J., Clark, K., Freedland, K.E., 1988b. The relationship between heart rate variability and depression in patients with coronary artery disease. J. Psychosom. Res. 32, 159]164. Cohen, S., Mermelstein, R., Kamarck, T., Hoberman, H.M., 1985. Measuring the functional components of social support. In: Sarason, I.G., Sarason, B.R. ŽEds.., Social Support: Theory, Research and Applications. Martinus Nijhoff, Dordrecht, Netherlands, pp. 73]94. Evans, D.L., Leserman, J., Pedersen, C.A., et al., 1989. Immune correlates of stress and depression. Psychopharmacol. Bull. 25, 319]324. Fielding, R., 1991. Depression and acute myocardial infarction: a review and reinterpretation. Soc. Sci. Med. 32, 1017]1027. Frasure-Smith, N., Lesperance, F., Talajic, M., 1995. Depres´ sion and 18-month prognosis after myocardial infarction. Circulation 91, 999]1005. Friedman, H.S., Booth-Kewley, S., 1987. The disease-prone personality: a meta-analytical view of the construct. Am. Psychol. 42, 539]555. Girdler, S.S., Hinderliter, A.L., Light, K.C., 1993. Peripheral adrenergic receptor contributions to cardiovascular reactivity: influence of race and gender. J. Psychsom. Res. 37, 177]193. Harris, W.S., Schoenfield, C.D., Weissler, A.M., 1967. Effects of adrenergic receptor activation and blockade on the systolic pre-ejection period, heart rate and arterial pressure in man. J. Clin. Invest. 46, 1704]1714. Hayano, J., Sakakibara, Y., Yamada, M., et al., 1991. Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects. Am. J. Cardiol. 67, 199]204. Jennings, J.R., McKnight, J.D., 1994. Inferring vagal tone from heart rate variability. Psychosom. Med. 56, 194]196. Kamarck, T.W., Manuck, S.B., Jennings, J.R., 1990. Social support reduces cardiovascular reactivity to psychological challenge: a laboratory model. Psychosom. Med. 52, 42]58. Kleiger, R.E., Miller, J.P., Bigger, T.J., Jr., Moss, A.J., Multicenter Post-Infarction Research Group 1987. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am. J. Cardiol. 59, 256]262. Krantz, D.S., Hedges, S.M., Gabbay, F.H., Klei, et al., 1994. Triggers of angina and ST-segment depression in ambulatory patients with coronary artery disease: evidence for an uncoupling of angina and ischemia. Am. Heart J. 128, 703]712.
Krittayaphong, R., Cascio, W.E., Light, K.C. et al., 1997. Heart rate variability in patients with coronary artery disease: differences in patients with higher and lower depression scores. Psychosom. Med. 59, 231]235. Lahmeyer, H.W., Bellur, S.N., 1987. Cardiac regulation and depression. J. Psychiatr. Res. 21, 1]6. Lesperance, F., Frasure-Smith, N., Talajic, M., 1996. Major ´ depression before and after myocardial infarction: its nature and consequences. Psychosom. Med. 58, 99]110. Orth-Gomer, K., Unden, A.-L., 1990. Type A behavior, social support, and coronary risk: interaction and significance for mortality in cardiac patients. Psychosom. Med. 52, 59]72. Mittleman, M.A., Maclure, M., Sherwood, J.B., et al., 1995. Triggering of acute myocardial infarction by episodes of anger. Circulation 92, 1720]1725. Rudorfer, M.V., Ross, R.J., Linnoila, M., Sherer, M.A., Potter, W.Z., 1985. Exaggerated orthostatic responsivity of plasma norepinephrine in depression. Arch. Gen. Psychiatry 42, 1186]1192. Lepore, S.J., Mata Allen, K.A., Evans, G.W., 1993. Social support lowers cardiovascular reactivity to an acute stressor. Psychosom. Med. 55, 518]524. Sheffield, D., Krittayaphong, R., Cascio, W.E. et al., 1998. Heart rate variability at rest and during mental stress in patients with coronary artery disease: differences in patients with high and low depression scores. Int. J. Behav. Med. Žin press.. Sherwood, A., Dolan, C.A., Light, K.C., 1990. Hemodynamics of blood pressure responses to active and passive coping. Psychophysiology 27, 656]668. Simonsick, E.M., Wallace, R.B., Blazer, D.G., Berkman, L.F., 1995. Depressive symptomatology and hypertension-associated morbidity and mortality in older adults. Psychosom. Med. 57, 427]435. van den Meiracker, A.H., Tulen, J.H.M., Man in’t Veld, A.J., Balk, A.H.M.M., van Steenis, H.G., Schalekamp, M.A.D.H., 1993. Blood pressure and heart rate variability in clinical models of cardiac denervation, sympathicolysis and sympathico- parasympathicolysis. J. Hypertension 11, S152]S153. Veith, R.C., Lewis, N., Linares, O.A., et al., 1994. Sympathetic nervous system activity in major depression: basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch. Gen. Psychiatry 51, 411]422. Vybiral, T., Bryg, R.J., Maddens, M.E., Boden, W.E., 1989. Effect of passive tilt on sympathetic and parasympathetic components of heart rate variability in normal subjects. Am. J. Cardiol. 63, 1117]1120. Williams, J.B.W., 1988. A structured interview guide for the Hamilton Depression Rating Scale. Arch. Gen. Psychiatry 45, 742]747. Williams, R.B., Barefoot, J.C., Califf, R.M., et al., 1992. Prognostic importance of social and economic resources among medically treated patients with angiographically documented coronary artery disease. J. Am. Med. Assoc. 267, 520]524.
Enhanced cardiovascular and catecholamine responses in women with depressive symptoms Kathleen C. LightU , Rupa V. Kothandapani, Michael T. Allen Departments of Psychiatry and Psychology, Uni®ersity of North Carolina, CBa7175, Medical Building A, Chapel Hill, NC 27599-7175, USA Di®ision of Education and Psychology, Uni®ersity of Southern Mississippi-Gulf Coast, 730 East Beach Boule®ard, Long Beach, MS 39560, USA Accepted 30 September 1997
Abstract To test the hypothesis that cardiovascular and sympathetic nervous system responses before and during behavioral stressors are exaggerated among subjects with depressed mood who do not have clinical depressive disorder. Sixty healthy women aged 18]49 were initially asked to complete the Beck Depression Inventory ŽBDI.. The 15 with the highest ŽDepressive Symptom group. and the 15 with the lowest BDI scores ŽControl group. underwent stress testing including baseline, postural challenge, a speech task describing responses to a recent anger-arousing experience and recovery. Both systolic and diastolic blood pressure levels were higher in the Depressive Symptom group during baseline, challenges and recovery. This group also showed shorter pre-ejection period Ža marker of enhanced cardiac sympathetic activation. and lesser heart rate variability across all test periods. During the speech task only, the Depressive Symptom group exhibited greater increases in plasma norepinephrine and higher cardiac output responses associated with decreased interbeat interval Žfaster heart rate.. These results support the a priori hypothesis regarding enhanced sympathetic and cardiovascular activity. Finally, the BDI scores correlated very highly with lack of perceived emotional social support, reinforcing prior research on the linkage between social isolation and severity of depressive symptoms. Q 1998 Elsevier Science B.V. Keywords: Depression; Sympathetic nervous system; Stress; Plasma norepinephrine; Cardiovascular system; Social support
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Corresponding author.
0167-8760r98r$19.00 Q 1998 Elsevier Science B.V. All rights reserved. PII S0167-8760Ž97.00093-7
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1. Introduction Depression is one of several psychological factors which have been shown to relate to increased risk of developing cardiovascular disease and to greater morbidity and mortality in patients with confirmed coronary heart disease ŽCHD. or myocardial infarction ŽMI. ŽCarney et al., 1988a, 1995a; Friedman and Booth-Kewley, 1987; Fielding, 1991.. Most recently, prospective research by Frasure-Smith and colleagues ŽFrasure-Smith et al., 1995; Lesperance et al., 1996. has shown that ´ both major depression and also depressed mood as indicated by a moderately increased score on the Beck Depression Inventory ŽBDI. were predictive of increased risk of subsequent mortality in patients tested while in hospital for recent myocardial infarction ŽMI.. Most of the deaths among patients with high BDI scores who did not meet criteria for major depression were observed to occur in patients who lacked emotional social support. Social isolation and lack of a confidant have been related to increased risk of cardiovascular death in numerous other investigations ŽOrth-Gomer and Unden, 1990; Williams et al., 1992; Berkman et al., 1992.. The study by Frasure-Smith et al. Ž1995. also indicated that the combination of a high score on the BDI when combined with more frequent premature ventricular complexes ŽPVCs. was associated with a tenfold increase in risk of early death. This observation was interpreted as consistent with the hypothesis that the high depressed mood in these patients might be accompanied by physiological changes including altered cardiac autonomic balance which might potentially trigger fatal arrhythmias or sudden cardiac death in patients with electrocardiographic evidence of increased vulnerability. Other research by Carney et al. Ž1988b, 1995b. documented that patients with CHD who meet criteria for major depression demonstrate significantly decreased heart rate ŽHR. variability on 24-h Holter monitoring. Decreased HR variability has been documented to be a powerful predictor of later cardiac death in patients with CHD and is interpreted by many investigators as evidence of altered cardiac autonomic balance ŽKleiger et al., 1987; Hayano et
al., 1991.. Recently, Krittayaphong et al. Ž1997. found that patients with confirmed CHD who showed high depression scores on the MMPI, but without clinical depression, demonstrated higher average HR levels and decreased HR variability over 24 h of Holter monitoring as well. A number of studies have confirmed that HR variability is altered as a function of differences in parasympathetic and sympathetic nerve activity to the myocardium ŽVybiral et al., 1989; Hayano et al., 1991; van den Meiracker et al., 1993.. Decreased HR variability may result from a change in the balance between the two autonomic systems modulating HR. An increase in cardiac sympathetic tone either with or without a concomitant decrease in parasympathetic tone can result in decreased HR variability due to increased sympathetic relative to parasympathetic drive ŽJennings and McKnight, 1994.. Although a faster or slower average HR level by itself is not a clear indicator of the autonomic mediation involved, decreased HR variability due to increased sympathetic relative to parasympathetic tone is normally associated with an increase in average HR level. Clinical depression in patients presumed free of CHD has been associated with a increase in 24-h mean HR levels ŽLahmeyer and Bellur, 1987. and enhanced adrenergic activity of this same patient group has been documented as exaggerated plasma norepinephrine ŽNE. responses to orthostatic challenge ŽRudorfer et al., 1985. and increased rate of NE release from sympathetic nerves Žindexed as NE appearance into an extravascular compartment. ŽVeith et al., 1994.. Although symptoms of depressed mood have been related to altered immune status, measures known to be sensitive to adrenergic activity ŽEvans et al., 1989., direct assessment of cardiovascular andror catecholamine responses to behavioral stressors in healthy individuals with depressed mood has been absent to date. Among cardiovascular measures sensitive to cardiac sympathetic activity Žbeta-1 receptor mediated increases in HR and contractile force., one of the best non-invasive indexes is the pre-ejection period ŽPEP.. Shortening of the PEP with increased HR level has been shown to result from increased efferent activity of the cardiac sympathetic nerves and infusion of
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isoproterenol, but not as a result of vagal blockade or atrial pacing ŽHarris et al., 1967; Binkley and Boudoulas, 1986.. PEP responses to behavioral challenges have been shown to characterize individuals who are high cardiac reactors to behavioral stress ŽSherwood et al., 1990. but has not been examined to date in relation to depressed mood. These findings led us to consider the following questions. First, is there the same association between depressed mood and reduced heart rate variability as well as other indicators of altered cardiovascular activity in healthy individuals free of CHD as in patients with such disease? Second, is depressed mood also associated with more definitive indexes of altered autonomic function, such as decreased PEP and increased plasma epinephrine ŽE. and NE response? Third, are these signs of autonomic alterations enhanced by exposure to psychological stress? Lastly, to what extent do these signs of altered peripheral sympathetic function relate similarly to lack of adequate social support? This investigation was intended to serve as an initial attempt to address these questions, using a sample of healthy young women aged 18]39 years. Women were selected for study because in such an initial investigation, it was desirable to reduce other potential sources of intersubject variability, such as gender, and because depression and depressed mood are reported to be more prevalent among women ŽLesperance et al., 1996.. ´ 2. Materials and methods 2.1. Subjects Sixty healthy women aged 18]49 were recruited to participate in a study of mood and stress response through local advertisements. Exclusionary criteria included: medical history of established hypertension; heart disease or other chronic illness; prior diagnosis of major or minor depressive disorder; current use of antidepressant or anti-anxiety medication; oral contraceptives; or any medication known to affect autonomic or cardiovascular activity. The protocol was ap-
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proved by our institutional review board and all women provided informed consent in writing before participating. All 60 subjects completed the Beck Depression Inventory ŽBDI., a 21-item instrument used to assess depressed mood. Subjects were paid $5 for completing screening procedures and the BDI. Then, the 15 women whose BDI scores fell into the top quartile Žrange 8]31, mean 16.7" 2.0. were classified as the Depressive Symptom group and the 15 subjects whose BDI scores were in the lowest quartile Žrange 0]4, mean 2.2" 0.3. were retained as the Control group. Each woman’s depressed mood status was not revealed to them at any point in the study, to avoid any confounding effects of labeling. The Depressive Symptom and Control women did not differ in age Ž32.5" 9.9 vs. 30.1" 9.0 years., height Ž64.8" 2.7 vs. 66.4 " 2.3 inches., weight Ž141.1 q26.5 vs. 142.2" 15.8 lbs., or ethnic group proportions Žtwo Black: 13 Whiterother vs. one Black: 14 Whiterother.. The 15 Depressive Symptom and 15 Control subjects subsequently underwent further testing, including further assessment of depression status using the Hamilton Depression Rating Scale, a scale which has been widely used for patient selection and assessment of treatment benefits in studies of clinical depression ŽWilliams, 1988.. To confirm that none of the Depressive Symptom subjects currently met criteria for clinical depression, the protocol dictated that any subject with a Hamilton Depression score of 15 or higher would undergo a clinical diagnostic interview; however, no subject exceeded a Hamilton score of 12 Žout of a maximum of 56.. No subject had a history of any psychiatric disorder; however, no additional screening for anxiety disorders or other clinical psychiatric disorder was performed. These subjects also completed a questionnaire on current emotional social support, the ‘appraisal support’ subscale of the Interpersonal Support Evaluation List ŽISEL. ŽCohen et al., 1985.. In our previous research, high appraisal social support indexed by this ISEL subscale was related to reduced clinic and ambulatory blood pressure ŽBP. levels in highly hostile men and women ŽBrownley et al., 1996..
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The Depressive Symptom and Control subjects also underwent a 90-min stress testing session as detailed below. They received an additional $25 for this testing. 2.2. Physiological recording procedures Auscultatory BP levels were determined using a custom designed and built automated cuff inflationrdeflation system attached to a standard inflatable arm cuff positioned around the subject’s left arm. Cuff pressure and Korotkoff sounds obtained using a piezoelectric microphone over the brachial artery under the lower edge of the cuff were recorded as analog signals using the Videograph II computer-based chart recorder system. Systolic ŽSBP. and Diastolic ŽDBP. levels were defined as the pressure at the onset ŽPhase 1. and disappearance ŽPhase 5. of Korotkoff sounds. A series of three to five BP readings were recorded immediately after instrumentation with an additional signal corresponding to onset and disappearance of Korotkoff sounds as heard through a stethoscope by a trained assistant; these were used to standardize subsequent scoring to match the stethoscopic determinations. Impedance cardiography was utilized for noninvasive estimation of stroke volume ŽSV.. A Minnesota Impedance Cardiogaph ŽModel 304B. was used in conjunction with a tetrapolar band electrode configuration ŽCleartrace No. 1700. with two bands encircling the upper and lower neck and two located around the thorax. Impedance and electrocardiogram ŽECG. signals Žobtained by means of external chest electrodes. were processed on-line and subsequently edited for accuracy using the Cardiac Output Program ŽCOP, Microtronics Inc.. software which was developed and validated in our laboratory. For each minute of interest, a 40-s continuous sample of waveforms was processed to generate an ensemble-averaged cardiac cycle. This ensemble average was used to quantify the PEP, an index of cardiac sympathetic activity ŽHarris et al., 1967., SV Ždetermined via the Kubicek equation. and heart rate ŽHR.. SV and HR were used to derive cardiac output ŽCO. and when combined with concurrently obtained mean arterial BP, to calculate
total peripheral resistance using standard formulas Žfor details see Sherwood et al., 1990.. Heart rate variability during the baseline and task periods was derived from the 40-s continuous ECG data obtained and processed by the COP software. Interbeat intervals ŽIBIs. were first calculated from COP data and, from these, the ‘mean successive difference’ ŽMSD. was calculated for each sample based on the average of the differences between each interbeat interval and the one which followed it. Hayano et al. Ž1991. have confirmed through direct manipulation of vagal and sympathetic input that the MSD statistic is highly sensitive to alterations in autonomic balance and as strong or stronger than frequency domain measures obtained via spectral analysis in indexing changes in cardiac sympathetic and vagal tone. 2.3. Experimental protocol After instrumentation and stethoscopic readings Ž20]25 min., the subject continued to rest quietly in a seated position for a baseline period of 21 min. Following the baseline rest, the subject went through the Postural Challenge, rising from sitting to standing for 3 min. After being reseated for 5 min and a second 5-min instruction period, subjects underwent the Speech task, where she was asked to talk for 3 min about a recent personal incident that had made her angry. A preparatory period of 2 min preceded the speech. Following the speech, subject rested and recovered for 11 min. Cardiovascular responses were obtained every other min Žmin 1, 3, 5, etc.. during each of these events. Blood samples were drawn at the end of the baseline period and after each of the two stressors to assess plasma E and NE responses. 2.4. Plasma catecholamine assays Blood was drawn into EDTA tubes kept on ice and centrifuged to separate plasma within a few minutes after collection. Plasma was pipetted into tubes, rapidly frozen and maintained at y 608C until assayed. The assay procedure involved extraction of catecholamines from 1.0 ml of plasma
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with activated lumina, injection of the acid extract onto a reverse phase C-18 column and separation with a mobile phase of 2.6% acetonitrile and a 0.2-g sodium octane sulfonate in phosphaterEDTA buffer pumped at 1 mlrmin and 1600 psi ŽLC 10AD Pump, Shimadzu Corp, Kyoto, Japan.. The E and NE levels were detected with an ESA Coulochem Electrochemical Detector ŽESA, Bedford, MA, USA., recorded using the PE-Nelson Analytical System and analyzed with PE-Nelson Turbochrome Software ŽCupertino, CA, USA.. The lower limit of quantification with this system was 5 pgrml and intra- and inter-assay coefficients of variation were less than 10%. 2.5. Data analyses Cardiovascular data were averaged during the conclusion Žmin 17, 19 and 21. of the baseline period, during minute 1 and 3 of each of the two challenges and during the recovery period Žmin 1, 3, 5, 7, 9 and 11.. For each cardiovascular measure ŽSBP, DBP, PEP, CO, TPR, IBI and MSD., a separate repeated measures analysis of variance ŽANOVA. was performed using a two ŽGroup: Depressed vs. Control. by four ŽTime Periods: Baseline vs. Posture vs. Speech Challenge vs. Recovery. design. For SV, CO, TPR, SBP, DBP and MSD, these analyses were performed with body surface area ŽBSA. as a covariate. Indexing for BSA is recommended for SV, CO and TPR measures; also, increased BSA has been associated with increased BP in other studies and this same relationship was seen in the present sample Ž P0.007.. Increased BSA was also found to be related to decreased MSD in this sample Ž P0.025.. When the Group= Time Periods effect was significant or approached significance using the more conservative MANOVA solution, subsequent least square means comparisons during each individual time period were used to determine whether groups differed only during the stressors. Plasma E and NE levels were compared at baseline between Groups by means of t-tests and results during each task were individually examined as percent increases from baseline. These analyses involved reduced degrees of freedom since inability to obtain an adequate blood
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sample or technical problems with the assay led to having complete catecholamine data in only 10 Depressed Mood and nine Control subjects. Lastly, the relationship of social support to depressed mood was assessed using Pearson correlation coefficients, to determine whether effects of depressed mood and social isolation may be substantially overlapping. 3. Results 3.1. Cardio®ascular responses The Depressive Symptom group was found to have higher blood pressure levels than the Control group both at rest and during the two stressors. Repeated measures ANCOVAs yielded a significant main effect of Group for SBP and DBP Ž F1,27 s 4.62 and 4.81, P- 0.05; see Figs. 1 and 2.. Both groups showed approximately equivalent increases in SBP and DBP to the two stressors and as a result the Group= Time Periods interactions for these variables were non-significant Ž P) 0.20.. The subjects with Depressive Symptoms also demonstrated consistently shorter PEP and reduced heart rate variability assessed by MSD across rest and stressor periods compared with control subjects ŽMain effect of Group, F1,28 s 4.21 and F1,27 s 4.27, P- 0.05., suggesting a general increase in cardiac sympathetic tone relative to parasympathetic tone. As with the BP measures, for PEP and MSD analyses, the interaction with Time Periods was non-significant, indicating no further enhancement of group differences during stress Žsee Figs. 3 and 4.. For CO and TPR analyses, the main effect of Groups was non-significant Ž P) 0.20.. For CO, however, the Group= Time Periods interaction was only marginally significant Ž P- 0.068.. Nevertheless, based on a priori hypotheses, subsequent comparisons were made separately at each time period. These comparisons indicated no group differences during Baseline, Posture Challenge or Recovery Ž P) 0.30., but during the Speech task, the Depressive Symptom subjects had higher CO than the control subjects Ž F1,27 s 4.72, P- 0.05; see Fig. 5.. This group difference selectively during the Speech task was due to an
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Fig. 1. Systolic blood pressure ŽSBP. levels adjusted for body surface area in the Depressive Symptom group are significantly higher than in the Control group across all task periods Ž P- 0.05..
increase in CO from baseline to speech among the Depressed group Žfrom 7.45 to 7.94 lrmin, P- 0.05. while the Control group showed essentially no change in CO during speech Žfrom 6.88 to 6.70 lrmin, Ps ns.. To determine whether these group differences in CO responses to the Speech task were due to increased HR or SV among the Depressive Symptom group Žthe two physiological determinants of CO., results of group comparisons of IBI Žthe inverse of HR. and SV were examined. SV responses of the two groups did not differ across any of the time periods Ž P) 0.30.. For IBI, there was a strong trend toward shorter IBI Žfaster HR. in the Depressive Symptom group across all time periods Ž F1,28 s 3.72, P- 0.064.. Like the results for CO, for IBI, group differences were evident only during the Speech task Ž F1,28 s 4.62, P- 0.05., indicating
Fig. 2. Diastolic blood pressure ŽDBP. levels adjusted for body surface area in the Depressive Symptom group are significantly higher than in the Control group across all task periods Ž P- 0.05..
Fig. 3. Pre-ejection period ŽPEP. levels in the Depressive Symptom group are significantly decreased compared with the Control group across all task periods Ž P - 0.05..
that higher HR during the Speech task contributed to the increased CO responses of the Depressive Symptom group Žsee Fig. 6.. 3.2. Plasma catecholamine responses Baseline levels of plasma E and NE did not differ reliably between the Depressive Symptom and Control groups Ž44.8 vs. 36.3 and 225 vs. 211 ngrml, P) 0.40.. For subsequent analyses involving percent changes in NE from baseline levels, a significant main effect of Groups and a significant Group= Time Periods interaction were obtained Ž F1,17 s 4.17, P- 0.05 and 6.65, P- 0.02.. The Depressive Symptom subjects showed greater increases in plasma NE to the Speech task Žq59.9% vs.q15.5%, P- 0.012. and a trend toward greater increase in NE to the Posture Challenge Žq37.7% vs.q19.7%, P) 0.10. Žsee Fig. 7.. For plasma E
Fig. 4. Heart rate ŽHR. variability levels indexed by the mean successive difference ŽMSD. in the Depressive Symptom group are significantly decreased compared with the Control group across all task periods Ž P - 0.05..
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Fig. 5. Cardiac output responses adjusted for body surface area in the Depressive Symptom group are greater than in the Control group during the Speech task Ž P- 0.05. but not during the Postural Challenge ŽStand..
responses to stressors, the direction of response to the Speech task differed between the two groups, with Depressed subjects showing an increase and Control subjects showing a decrease from baseline, but this difference in plasma E response was non-significant Žq5.2% vs.y8.6%, P) 0.10.. Neither group showed an increase in plasma E in response to the Postural Challenge Ž0% vs.y13.2%, P) 0.10.. These results are consistent with the cardiovascular findings in indicating an increase in sympathetic nervous system activity in the subjects with Depressive Symptoms. 3.3. Relationship of low social support to se®erity of depressi®e symptoms To address the hypothesis that high scores on scales of depressive symptoms like the BDI may
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Fig. 7. Percent increase from baseline in plasma norepinephrine ŽNE. levels in the Depressive Symptom group is greater than in the Control group during the Speech task Ž P - 0.012. but not during the Postural Challenge ŽStand..
be related to lack of emotional social support, correlational analyses were performed to determine the association of ISEL appraisal support scores with BDI. Although we had hypothesized that depressive symptoms would be associated with low support, the strength of the inverse relationship between appraisal support and depression severity in this sample of healthy young women was greater than anticipated Ž r 29 s y0.82, P- 0.0001.. Thus, although our a priori hypotheses were directed at examining the relationship of depressive symptoms to altered cardiovascular responses, the extensive overlap of these symptoms with low support suggests that had we grouped our subjects on the basis of low vs. high social support from a confidante, our observed group differences would have been substantially the same. 4. Discussion
Fig. 6. Interbeat interval in the Depressive Symptom group is shorter Žindicating faster heart rate. than in the Control group during the Speech task Ž P- 0.05. but not during the Postural Challenge ŽStand..
In this sample of healthy young women, the presence of a subclinical depressive state as indicated by high scores on the Beck Depression Inventory was associated with several signs of enhanced peripheral sympathetic activity. The most definitive evidence was derived from plasma catecholamine responses to the stressors. The women with depressive symptoms demonstrated greater percent increases in plasma NE levels than women with few or no dysphoric symptoms in response to the stress of a simulated speech on
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a recent anger-arousing experience. They also showed directional trends toward higher plasma NE reactivity to the postural challenge and in plasma E reactivity to both tasks, although these were non-significant with the present small sample size and high inter-individual variability which is typical of these measures. Although baseline levels of plasma NE and E did not differ between the depressed and control subjects, there was other evidence of a generalized increase in sympathetic activity to the heart which was evident during both rest and stress. First, the women reporting depressive symptoms had increased SBP and DBP and shorter PEP levels both at rest and during stress. Decreased PEP is associated with increased sympathetic drive on the myocardium ŽHarris et al., 1967; Binkley and Boudoulas, 1986.. Although there is no ‘pure’ index of increased centrally mediated efferent sympathetic nerve activity to the heart which can be obtained non-invasively, PEP is widely viewed as one of the better indirect indexes of such activity. The magnitude of difference between the PEP levels of the women with vs. without depressive symptoms was in fact very similar to the differences in PEP observed before vs. after beta-blockade with propranolol in a prior study in our laboratory ŽGirdler et al., 1993.. Furthermore, this interpretation of augmented adrenergic drive on the heart is strengthened by the findings of decreased HR variability as assessed by the MSD comparisons. Since the depressed group showed reduced HR variability, this suggests an alteration of the balance between sympathetic and parasympathetic tone influencing HR. When decreased HR variability is present together with an increase in HR level, as reflected by the decreased MSD together with the shorter mean IBI observed in these women with subclinical depressive symptoms, the most plausible explanation for this decrease in HR variability is an enhancement of cardiac sympathetic activity relative to vagal tone. The sum of the evidence from the plasma NE and increased HR and CO during the speech stressor and the generalized decrease in HR variability and shortened PEP in these healthy young women with subclinical depression indicates an increase on tonic sympathetic activity to the heart
and an increase in sympathetic responsivity to behavioral stress. These effects are similar to the observations of increases in both tonic and reactive NE measures in patients with major clinical depression ŽRudorfer et al., 1985; Veith et al., 1994.. They also document the similarity of healthy young adults with subclinical depression and older CHD patients with depression or depressed mood in regard to increased mean HR with decreased HR variability ŽCarney et al., 1988b, 1995b; Krittayaphong et al., 1997.. Thus, the alterations in adrenergic function associated with subclinical depression appear to be independent of the effects of the advanced cardiovascular alterations seen in the CHD patients; it is a primary rather than a secondary physiological dysregulation. Nevertheless, it is obvious that symptoms of depression may be magnified by the stress of CHD or any chronic illness and may be directly precipitated in vulnerable individuals by a sudden worsening of symptoms and prognosis such as after an acute MI ŽLesperance et al., 1996.. ´ These interpretations must be qualified by two study limitations. First, although the Hamilton was used to screen for clinical depression, no full psychiatric screening was performed to rule out the possibility that some subjects might have met criteria for anxiety disorders or other clinical psychiatric disorders. Second, both the modest sample size and the restriction of the sample to young women indicates a need for further examination of these relationships in a larger and more diverse sample. The finding that these young women with depressive symptoms had higher blood pressure than control women at rest as well as during acute stressors indicates that homeostatic mechanisms regulating blood pressure may have undergone a chronic resetting, allowing blood pressure to be maintained at a higher set-point. Further increments of this kind could potentially lead to sustained hypertension. It is also clear that these kinds of alterations in peripheral sympathetic activity can enhance risk of developing hypertension-related morbidity ŽSimonsick et al., 1995. and both coronary ischemia and arrhythmia ŽCarney et al., 1995a; Cameron, 1996.. Increased efferent sympathetic drive on the myocardium may
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alter ventricular fibrillation threshold in vulnerable patients, which may help explain the tenfold increase in mortality observed by Frasure-Smith et al. Ž1995. in post-MI patients with both high BDI scores and a high rate of PVCs. Increased plasma NE and high HR may increase the likelihood of vasospasm in damaged and partially occluded coronary arteries, thus leading to an increasing risk of myocardial ischemia possibly leading to angina or even MI due to both increased myocardial demand and diminished supply ŽKrittayaphong et al., 1997.. The present results and those of Sheffield et al. Ž1998. in patients with CHD suggest that there may be an increased impact of life stressors in CHD patients with depressive symptoms as well. Mental stress has been found to be a potent trigger for cardiac events in patients with documented CHD, presumably in part through surges in sympathetic activity ŽBrackett and Powell, 1988; Krantz et al., 1994; Mittleman et al., 1995.. The connection between severity of depressive symptoms and lack of adequate social support was also reinforced by the present findings. In these healthy young women, there was a very strong inverse correlation between the magnitude of perceived emotional Žconfidante. support and depressive symptoms. Previous investigations have shown associations between low social support and cardiovascular morbidity which are strikingly similar to observed associations between depression and the same morbid health outcomes ŽOrth-Gomer and Unden, 1990; Berkman et al., 1992; Williams et al., 1992.. Since social isolation can promote dysphoric mood and conversely feeling sad and losing interest in usual activities Žthe two central components of depression. may tend to reduce the frequency of contacts with supportive friends and relatives, it may not be possible to fully separate the effects of these two psychosocial factors. Our research group and others ŽOrth-Gomer and Unden, 1990; Brownley et al., 1996. have found that adequate social support may reduce the cardiovascular changes associated with long-term stress of a hostile or Type A behavior pattern, and other studies ŽKamarck et al., 1990; Lepore et al., 1993. have shown the benefits of immediately available support on acute
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cardiovascular responses to lab stressors. Further study of depression and depressed mood must most appropriately also focus on social support measures and vice versa. 5. Summary In summary, among healthy young women who had no current or prior history of clinical depression, the presence of depressive symptoms Žsubclinical depression. was related to increased blood pressure, evidence of increased adrenergic drive on the heart both at rest and during behavioral stressors and an increase in cardiac output and plasma norepinephrine responses to a speech about a recent anger-arousing experience. These results indicate that peripheral adrenergic dysregulation, previously reported in clinical depression, is detectable in subjects with much milder dysphoric symptoms. The findings also add to observations on the potential physiological mechanisms which may contribute to the documented increase in morbidity and mortality in patients with coronary heart disease who have clinical depression or milder depressive symptoms. Lastly, these subjects demonstrated a direct correspondence between the severity of reported depressive symptoms and the lack of emotional social support, extending prior research on the linkage between these two psychosocial factors. References Berkman, L.F., Leo-Summers, L., Horwitz, R.I., 1992. Emotional support and survival after myocardial infarction: a prospective population-based study of the elderly. Ann. Intern. Med. 117, 1003]1009. Binkley, P.F., Boudoulas, H., 1986. Measurement of myocardial inotropy. In: Leier C.V. ŽEd.., Cardiotonic Drugs: A Clinical Survey. Marcel Dekker, New York, pp. 5]48. Brackett, C.D., Powell, L.H., 1988. Psychosocial and physiological predictors of sudden cardiac death after healing of acute myocardial infarction. Am. J. Cardiol. 61, 979]983. Brownley, K.A., Light, K.C., Anderson, N.B., 1996. Social support and hostility interact to influence clinic, work and home blood pressure in Black and White men and women. Psychophysiology 33, 434]445. Cameron, O., 1996. Depression increases post-MI mortality: How? ŽEditorial comment.. Psychsom. Med. 58, 111]112. Carney, R.M., Freedland, K.E., Rich, M.W., Jaffe, A.S., 1995a. Depression as a risk factor for cardiac events in established
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