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Psychosomatic Medicine 68:675-683 (2006)
© 2006 American Psychosomatic Society

ORIGINAL ARTICLES

Depression and Stress Reactivity in Metastatic Breast Cancer

Janine Giese-Davis, PhD, Frank H. Wilhelm, PhD, Ansgar Conrad, Dipl-Psych, Heather C. Abercrombie, PhD, Sandra Sephton, PhD, Maya Yutsis, BA, Eric Neri, BS, C. Barr Taylor, MD, Helena C. Kraemer, PhD and David Spiegel, MD

From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California (J.G.-D., M.Y., E.N., C.B.T., H.C.K., D.S.); the Department of Clinical Psychology and Psychotherapy, Institute for Psychology, University of Basel, Basel, Switzerland (F.H.W.); the Department of Veterans Affairs Health Care System, Palo Alto, California (A.C.); the Department of Psychiatry, University of Wisconsin Medical School, Madison, Wisconsin (H.C.A.); and the Department of Psychological and Brain Sciences, University of Louisville, Louisville, Kentucky (S.S.).

Address correspondence and reprint requests to Janine Giese-Davis, PhD, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305. E-mail: jgiese{at}stanford.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Objective: Cancer-related distress due to the psychological and physical challenges of metastatic breast cancer (MBC) may result in symptoms of depression, which negatively affects quality and may influence quantity of life. This study investigated how depression affects MBC stress reactivity, including autonomic (ANS) and hypothalamic–pituitary–adrenal (HPA) axis function.

Method: Forty-five nondepressed and 45 depressed patients with MBC underwent a modified Trier Social Stress Test (TSST) while affect, cardiovascular, respiratory, and cortisol responses were measured.

Results: At study entry, depressed compared with nondepressed patients had significantly lower log cortisol waking rise levels (p = .005) but no other HPA differences. Positive affect (p = .025) and high-frequency heart-rate variability (lnHF) (p = .002) were significantly lower at TSST baseline in depressed patients. In response to the TSST, depressed patients reported significantly lower positive (p = .050) and greater negative affect (p = .037) and had significantly reduced lnHF (p = .031). In secondary analyses, at TSST baseline both low-frequency (lnLF) (p = .002) and very-low-frequency (lnVLF) (p = .0001) heart rate variability were significantly lower in the depressed group. In secondary analyses during the TSST, those who were depressed had significantly lower lnVLF (p = .008) and did not increase aortic impedance reactivity as much as did the nondepressed during the stressor (p = .005).

Conclusion: Depression in patients with MBC was associated with alterations in autonomic regulation, particularly reductions in respiratory sinus arrhythmia, a measure of cardiac vagal control, at baseline and during the TSST. In addition, depression was associated with blunted HPA response to awakening. Both MBC groups had relative cortisol hyporesponsiveness to acute stress.

Key Words: breast cancer • major depressive disorder • psychological stress • autonomic nervous system • cortisol • HPA axis

Abbreviations: ANS = autonomic nervous system; BMI = body mass index; BP = blood pressure; BRC = baroreflex control of heart rate; CO = cardiac output; CVD = cardiovascular disease; DBP = diastolic blood pressure; ECG = electrocardiogram; HDL = high-density lipoprotein; HPA axis = hypothalamic–pituitary–adrenal axis; HR = heart rate; HRSD = Hamilton Rating Scale of Depression; HRV = heart rate variability; ICG = impedance cardiogram; lnHF = natural log of high-frequency HRV; lnLF = natural log of low-frequency HRV; lnVLF = natural log of very low frequency HRV; LDL = low-density lipoprotein; MBC = metastatic breast cancer; MDD = major depressive disorder; ND = nondepressed; PANAS = Positive and Negative Affect Schedule; pCO2 = partial pressure of carbon dioxide; PEP = preejection period; RR interval = time between two consecutive R waves of the ECG; RSA = respiratory sinus arrhythmia; RSATF = transfer function respiratory sinus arrhythmia; SBP = systolic blood pressure; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TSST = Trier Social Stress Test; VLDL = very-low-density lipoprotein.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Patients with metastatic breast cancer (MBC) undergo a series of stressors: existential threat, arduous treatments, body changes, and adverse effects on ability to work and maintain social relationships. Up to 80% of patients with breast cancer report significant distress during initial treatment. Although this distress tends to abate with time, 20% to 45% exhibit psychological morbidity 1 to 2 years later, and 10% have severe maladjustment for as long as 6 years (1). Although the majority of patients with MBC may not meet criteria for a psychiatric diagnosis (2), diagnosis can often lead to or co-occur with affective disorders (3). In other populations, chronic depression may compromise ability to respond to stressors (4) and increase allostatic load (5), but few studies have examined these hypotheses in MBC.

Breast Cancer, Depression, and Survival
Depression may adversely affect cancer survival (6), so understanding its impact on physiology is important. Of 24 published studies, 15 find a significant association between higher depression and shorter time to recurrence or survival (7). Depression is also associated with aberrations in hypothalamic–pituitary–adrenal (HPA) function (8–11), which in turn has been linked with shorter survival in patients with MBC (12). Responses of depressed patients with MBC to acute stress in not only HPA, but parasympathetic, and sympathetic systems will increase our understanding of any additional physiological burden.

Abnormalities in the regulation of HPA function have been linked to depression (10,13), shorter cancer survival (12), and also poorer recovery from acute myocardial infarction (14). Although no known studies examine respiratory sinus arrhythmia (RSA) and cancer survival, depression (15,16) and shorter survival in patients with heart disease (17) have been associated with abnormalities in cardiovascular regulation, particularly lower levels of RSA. Depressed patients may also have less sensitivity to the anti-inflammatory aspects of cortisol, possibly leading to greater circulating levels of anti-inflammatory cytokines (18). Patients with primary breast cancer who are fatigued have greater cytokines (19), chronic cellular immune response (20), and flatter cortisol response to stress (21).

Depression and Autonomic Nervous System Function
Little research links MBC, depression, and autonomic nervous system (ANS) function. However, in other populations, depression is moderately associated with reduced parasympathetic control of cardiac activity (vagal withdrawal in depression across 13 studies [Cohen's d = 0.33]) (22). Depression is slightly associated with increased sympathetic control in a recent meta-analysis (systolic blood pressure [SBP]: d = 0.13; diastolic blood pressure [DBP]: d = 0.17) (23). Increased heart rate (HR), being dually influenced by sympathetic and parasympathetic factors, was moderately associated with depression (d = 0.37) (23).

Because many cardiovascular and hemodynamic functions are jointly influenced by sympathetic and parasympathetic input, it is necessary to use measures that tease apart the two branches: a) preejection period (PEP) is the interval between the onset of the electrocardiogram (ECG) Q wave to onset of left ventricular ejection time, which is inversely related to the amount of sympathetic activation of the heart (24); and b) RSA quantified by natural log of high-frequency heart rate variability (lnHF) corresponds to the magnitude of rhythmic oscillations in heart rate accompanying breathing, which is related to the amount of vagal activation of the heart (25) and parasympathetic function. Thus, PEP and lnHF were chosen as our primary ANS measures.

Depression and Hypothalamic–Pituitary–Adrenal Axis Function
Depression has been characterized by a state of chronic HPA activation in other populations (13,26,27) with flattening of diurnal variation (8–10). Some patients with major depressive disorder (MDD) have high basal glucocorticoid levels when compared with nondepressed patients (4,13), although recent evidence suggests that those with nonpsychotic depression have low cortisol levels (28,29), and other studies have found no differences (4).

In a recent meta-analysis of stress tasks (4), patients with MDD more often had blunted cortisol and/or ACTH responses (18,30), although not always, and greater depression severity was associated with elevated cortisol during recovery (4,31). Thus, if depressed patients with MBC respond similarly to stress, it may reduce their capacity to mobilize an adequate cortisol response and to recover in the face of stressors.

Based on these mixed results, we hypothesized that depressed patients with MBC would show flattened diurnal cortisol levels, higher waking level, aberrations in waking rise, decreases in cortisol reactivity to social stress, with increased sympathetic (PEP) and decreased parasympathetic (RSA) tone. Patients were studied during baseline rest and Trier Social Stress Test (TSST) reactivity (32). We also explored a wide variety of hemodynamic, autonomic, and respiratory measures and cortisol recovery after the TSST to generate hypotheses for further study.


   METHOD
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Participants
This study was approved by the Stanford Institutional Review Board and conformed to HIPAA regulations. Ninety women with MBC completed baseline cortisol and questionnaires, the Structured Clinical Interview for DSM-IV (SCID) (33), and the TSST for this study between August 13, 2002, and November 30, 2004. One hundred seven women with MBC were eligible and signed consent from a total pool of 221. Twenty-nine were ineligible, 83 not interested, and two died before the study began. Of the remaining 107, eight dropped out, leaving 99. Nine participants did not complete the TSST as a result of busy schedules/distance (6) and cancer progression (3). Referrals came from Stanford and Bay Area oncologists, responses to newspaper advertisements, and word of mouth from study volunteers. Women could earn as much as $500 for their completion of the entire study protocol.

Inclusion criteria were metastatic or recurrent breast cancer, a Karnofsky rating of at least 70%, residence within the Greater San Francisco Bay Area, and proficiency in English to be able to complete questionnaires and the TSST. Exclusion criteria were other active cancers within 10 years (excepting basal cell or squamous cell carcinomas of the skin or in situ cancer of the cervix), positive supraclavicular lymph nodes as the only metastatic lesion, a concurrent medical condition likely to influence short-term survival, utilization of a corticosteroid within the preceding month, or a history of major psychiatric illness for which the patient was hospitalized or medicated (with the exception of depression or anxiety).

Procedure
Patients with MBC participated in the TSST (32), a standardized social and cognitive stressor. On arrival, participants were fitted with physiological recording equipment. After a 5-minute baseline and calibration procedure for respiration belts, participants were told they would have 5 minutes to prepare a speech for a job interview. This was immediately followed by a 5-minute speech and 5 minutes of mental math. A panel of two evaluators provided no facial feedback in response to participants. Participants were then instructed to sit quietly for an hour without moving or speaking much. This procedure was modified from the original TSST to include a 5- (rather than 10-) minute speech preparation, calibration for respiration belts, and a 60- rather than 30-minute recovery. Patients also stayed in the same room (rather than changing rooms) throughout the procedure. They completed the state Positive and Negative Affect Schedule (PANAS) at baseline and after each test segment. We debriefed following saliva collection the next day.

Demographics and medical status were assessed by self-report. Medical status information was collected from both patients and their physicians.

Psychological Measures
Depression
Depression was assessed using the SCID (33). We included in our depressed group those with current diagnoses of MDD, dysthymia, and depressive disorder not otherwise specified (N = 17). We also included those women currently taking antidepressants except those prescribed primarily for sleep, even if they were not currently diagnosable with depression based on the SCID (N = 28). All but nine of those women met the SCID lifetime threshold for a diagnostic depression category. These nine women may have received a diagnosis of depression from a physician who prescribed the medication. In our depressed sample, so many of the women were taking antidepressants (77.8%) that we could not definitively examine those effects: 31.1% selective serotonin reuptake inhibitor (SSRI), 4.4% tricyclic, 2.2% bupropion, 24.4% serotonin–norepinephrine reuptake inhibitor (SNRI), 2.2% SSRI + tricyclic, 4.4% SSRI + bupropion, 2.2% SNRI + tricyclic, 4.4% SNRI + bupropion, and 2.2% St. John's Wort. Self-reported depression severity was measured with the Beck Depression Inventory (BDI) (34).

Perceived Stress Scale
The Perceived Stress Scale (PSS) measured global perception of stress during the previous month (35). We used a short version comprised of 10 5-point Likert-type items (0 = never to 4 = very often).

MOS-SF 36 Health Survey
The MOS-SF 36 Health Survey (36) assessed overall perceived health. It consists of 36 items representing eight health concepts: physical function, role disability resulting from physical health problems, bodily pain, general health perceptions, vitality, social functioning, role disability resulting from emotional problems, and general mental health.

Traumatic Events
Using the traumatic event screening query from the posttraumatic stress disorder (PTSD) SCID, each reported event was judged by two independent raters with expertise in traumatic stress. Overall coding designations based on the SCID included a) none = no report of experiences in response to the prompt, b) stressful = only events that were judged to not meet DSM-IV-TR A1 criteria for PTSD, and c) traumatic = one or more reported events was judged to meet PTSD A1 criteria. Events were coded separately and participants received the life event code reflective of the highest level of exposure they reported.

Positive and Negative Affect Scale
State emotions were measured with the PANAS (37), a Likert-type adjective list of emotions (1–5 = slightly to extremely).

Cardiovascular Risk Factors
Participants were assessed on common cardiovascular risk factors. These included self-report questions on history of heart disease, high blood pressure, stroke, and smoking. Blood panel tests included low-density lipoprotein (LDL; mg/dl), high-density lipoprotein (HDL; mg/dL), LDL/HDL, triglycerides (mg/dL), and cholesterol. We assessed lipid-lowering and antihypertensive medication by self-report. Body weight (in kilograms) and height (in meters) were obtained in a standing position with shoes removed and subjects wearing street clothes. These were used to calculate body mass index (BMI; in kg/m2). Waist/hip ratio was also assessed (38).

Physiological Measurements and Data Reduction
Cortisol
Saliva was collected at waking, 30 minutes later, and at 12:00 PM, 5:00 PM, and 9:00 PM for 2 consecutive days at study entry (at least 1 week before the TSST), the day of the TSST, and the day after the TSST. Patients were offered wrist-worn timers to prompt them at scheduled saliva collection times. Saliva collection swabs (Sarstedt, Inc., Newton, NC) were stored in medication event monitoring system bottles from AARDEX Ltd. so that exact times could be recorded electronically. The TSST was run in the late afternoon between 4:00 PM and 7:00 PM because past research demonstrates greater TSST HPA effect sizes for late afternoon sessions (39). Saliva samples during TSST were collected 10 times: on arrival before hookup, after hookup, after 5 minutes of baseline quiet sitting and 5 minutes of paced breathing before the speech instructions, after speech preparation, after speech and math stressors, and during recovery at 10, 20, 30, 45, and 60 minutes.

During home-based collections, participants were instructed to refrigerate samples. They were advised not to eat, drink, smoke, brush teeth, or use mouthwash for 30 minutes before collections and to postpone collection if they had mouth wounds. They were asked not to drink alcohol during the hours before or during days when saliva samples were collected.

Samples were stored at –70°C before laboratory centrifugation and duplicate assays for salivary cortisol using luminescence immunoassay (LIA) reagents provided by Immuno-Biological Laboratories, Inc. Hamburg, Germany (40). Assay sensitivity was 0.015 µg/dL. Intraassay variation on low, medium, and high controls averaged 2.78%, 10.45%, and 4.79%, respectively. The mean values of the low, medium, and high controls were 0.054 µg/dL, 0.228 µg/dL, and 0.863 µg/dL, respectively. The interassay coefficients of variation for the low, medium, and high controls were 10.9%, 10.5%, and 5.5%, respectively.

Cardiovascular and Respiratory Physiology
Placement of electrodes/sensors, data recording, and data reduction followed conventions and published guidelines (e.g., (25,41)). Physiological channels were sampled at 400 Hz. A standard lead II ECG was obtained. An impedance cardiograph (HIC-2000; Instrumentation for Medicine, Inc., Old Greenwich, CT) measured electrical impedance changes using four spot electrodes attached to the neck and thorax. A Finapres 2300 BP monitor (Ohmeda, Inc., Madison, WI) was used to obtain the continuous arterial pressure waveform at the second digit of the nondominant hand. Respiratory pattern data were measured using thoracic and abdominal bellows (Lafayette Instrument, Inc., Lafayette, IN) connected to pneumographic transducers (James Long Co., Inc., Caroga Lake, NY). Expiratory partial pressure of carbon dioxide (pCO2) was measured continuously through a cannula at the nostrils by a calibrated infrared capnograph (N-1000; Nellcor, Hayward, CA). An automatic blood pressure (BP) monitor (Dinamap 1846SX) measured BP with a cuff around the upper right arm. Inflation was triggered 2 minutes after onset of each test segment.

Physiological signals were analyzed and averaged for each 5-minute period using an integrated suite of biosignal analysis programs written in MATLAB (Mathworks, Inc., Natick, MA) that has been described elsewhere (42). Heart rate (HR) was measured from the ECG. PEP was calculated as the interval from the ECG Q-point to the impedance cardiogram (ICG) B-point. Stroke volume was calculated using the Kubicek formula and multiplied with HR to obtain cardiac output (CO). Systemic vascular resistance was calculated as [1/3 SBP + 2/3 DBP]/CO. Aortic characteristic impedance and arterial compliance were measured using Wesseling's pulse-contour analysis method (43,44). Rate-pressure product was calculated as HR x SBP. Calibrated thoracic and abdominal respiration channels were used to calculate tidal volumes and respiratory rate.

High-frequency (lnHF), low-frequency (lnLF), and very-low-frequency (lnVLF) power of heart period variability were computed as the natural logarithms of the summed power spectral density of time between two consecutive R waves of the ECG (RR interval) between 0.15 to 0.5 Hz, 0.07 to 0.15 Hz, and 0.0033 to 0.07 Hz, respectively. A respiration-controlled transfer function, adjusting the lnHF estimate of RSA for respiratory rate and depth alteration confounds (RSATF), was quantified by fast Fourier transform and the averaged periodogram method as the magnitude of the transfer function relating RR interval to lung volume oscillations at the prominent respiratory frequency (45). Baroreflex control of heart rate (BRC), a vagally mediated measure of the sensitivity of the baroreflex loop, was estimated as the magnitude of the transfer function relating the RR interval to systolic pressure oscillations at the prominent SBP frequency in the 0.07 to 0.15 Hz band (46). Spectral coherence for RSATF and BRC was at least 0.5. The lnLF power of SBP variability (Mayer-wave) was computed as the summed power spectral density of SBP between 0.07 to 0.15 Hz. BRC and Mayer-wave were estimated for baseline periods only, because these measures were unstable during stress periods.

Physiological data were reviewed by a senior psychophysiologist (F.H.W.) blind to patient information. Improbable or inconsistent values prompted reanalysis. Outliers more than 2 standard deviations from the group mean that appeared improbable for that individual or measure were eliminated. Less than 1% of data were excluded.

Data Analysis
In the TSST, psychophysiological signals were averaged for baseline, anticipation, speech, math, and the first two 5-minute segments of recovery. Cortisol data were log-transformed to stabilize the variance. Baseline cortisol slope was calculated by regressing cortisol values on time from awakening on all points for 2 days. Waking cortisol was the average of waking levels for 2 days. Waking rise was the 2-day average of the difference between the cortisol levels at waking and 30 minutes postwaking. Recovery at 9:00 PM on the day of the TSST was the difference score between the average log cortisol level at 9:00 PM during the 2-day baseline and the 9:00 PM cortisol level after the TSST. Recovery at wake and waking rise the next day were computed similarly.

A hierarchical linear model with group (depressed or nondepressed), time, and their interaction was used, assuming autoregressive covariance structure to examine differences in TSST response trajectories among groups (47). Baseline values were subtracted for each response in the trajectory. Baseline differences in psychosocial measures, demographic and medical variables, cortisol, and baseline TSST were examined with Mann-Whitney-Wilcoxon or {chi}2 tests. Based on the literature and hypotheses, a small number of primary variables were tested (positive and negative affect, log cortisol level, PEP, lnHF). These primary measures were relatively independent with only a moderate correlation between positive and negative affect and negligible correlations among the other variables; thus, we used a p < .05 criterion. We present an effect size for group comparisons (48).

For hypothesis generation, we also explored a comprehensive set of autonomic measures using p < .01 as the screening criterion. These exploratory measures included lnLF, lnVLF, RSATF, RR interval, SBP, DBP, rate-pressure product, CO, systemic vascular resistance, aortic characteristic impedance, arterial compliance, baroreflex control, Mayer-wave, respiratory rate, tidal volume, and pCO2. We report p values, but readers should be warned that with repeated testing there will be many false-positives.

We examined differences between depressed and nondepressed groups on smoking, alcohol consumption, and exercise. We found no significant differences at baseline or during the days of the TSST.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 
Demographic, Medical, and Psychological Measures
These were examined to ensure that significant group differences in our primary analyses could be attributed to depression. The depressed group was significantly higher than the nondepressed group only for depression-related measures: higher depression symptoms (BDI), lower total mental and physical scores (SF-36), more perceived stress (PSS), reports of greater psychiatric problems, and problems with sleep (Table 1).


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  		TABLE 1. Baseline Descriptive Statistics for Psychosocial, Cortisol, Demographic, and Medical Status Variables for Nondepressed (N = 45) and Depressed (N = 45) Groups

 

In addition, the depressed group had significantly shorter disease-free intervals and fewer ethnic minorities. We could not detect differences on other demographics (age at baseline, initial diagnosis, and recurrence, education, income, marital status, employment status), prognostic medical variables (time from initial diagnosis and from metastasis to study entry, estrogen and progesterone receptor status, site of metastasis, treatment with surgery, reconstruction, chemotherapy, radiation, and hormone therapy, and treatment within 2 months of TSST), or any cardiovascular risk factors (Table 1).

Baseline Trier Social Stress Test: Primary Measures
At TSST baseline, depressed patients reported significantly lower positive affect (PANAS) and exhibited lower levels of basal RSA (lnHF) than nondepressed (Table 2, Fig. 1).


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  		TABLE 2. Baseline of Trier Social Stress Test Descriptive Statistics and Mann-Whitney Tests for Nondepressed (N = 45) and Depressed (N = 45) Groups

 

Figure 16
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  		Figure 1. Panel of means of Positive and Negative Affect (PANAS), high-frequency (lnHF) and very-low-frequency (lnVLF) heart rate variability, aortic characteristic impedance (ACI), and preejection period (PEP) for depressed and nondepressed patients with metastatic breast cancer during baseline and Trier Social Stress Test (TSST). Depressed women were significantly lower on positive affect, lnHF, lnLF (not shown), and lnVLF at baseline. During the TSST, depressed women were significantly lower on positive affect, lnHF, and lnVLF (main effects); higher on negative affect (main effect); and lower on ACI (group x time interaction).

 

Baseline Trier Social Stress Test: Secondary Autonomic Nervous System Measures
In exploratory analyses, lnLF and lnVLF (Table 2, Fig. 1) were significantly lower in depressed patients, but we could not detect differences in basal RSATF, a measure adjusting RSA for respiratory confounds, indicating that sources of autonomic oscillatory activity other than respiration were compromised in this group and pointing to a more general autonomic inflexibility. No group differences were found for respiratory rate and tidal volume that could account for the observed between-individual variations in RSA.

Trier Social Stress Test Reactivity: Primary Measures
During the TSST, depressed patients reported significantly lower positive and higher negative affect than the nondepressed group (PANAS) (main effects for group, Table 3, Fig. 1). Analysis of RSA (lnHF) indicated that baseline differences, with depressed patients exhibiting significantly lower levels than nondepressed, were maintained during the TSST (group main effect: Table 3, Fig. 1). For all measures, significant effects for time (Table 3) indicated that participants responded to the speech and math stressors with affective, ANS, and cortisol increases.


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  		TABLE 3. Results of Mixed-Effects Model During Trier Social Stress Test for Nondepressed (n = 45) and Depressed (n = 45) Groups

 

Trier Social Stress Test Reactivity: Secondary Autonomic Nervous System Measures
In exploratory analyses, the significantly lower baseline level of lnVLF for depressed patients was maintained throughout the stressor (main effect for group, Table 3, Fig. 1). Hemodynamic stress reactivity in aortic characteristic impedance was significantly blunted in the depressed group (group x time interaction: Table 3, Fig. 1). The nondepressed group reacted with greater aortic characteristic impedance (arterial "stiffness") during the time of the stressor despite starting at the same level.

Hypothalamic–Pituitary–Adrenal Axis Activity
Depressed compared with nondepressed women had a lower 2-day average baseline waking rise in log cortisol level (Table 1, Fig. 2). However, no other differences in cortisol measures could be detected between groups at baseline, during the TSST, or during recovery. A significant effect for time (Table 3) indicated that log cortisol levels increased in response to the speech and math stressors for both groups with the typical delayed peak at approximately 20 minutes poststress (Fig. 2).


Figure 26
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  		Figure 2. Panel of median cortisol during 2-day diurnal baseline at waking, wake + 30 minutes, 12:00 PM, 5:00 PM, and 9:00 PM and mean cortisol response during baseline and Trier Social Stress Test (TSST) for women with metastatic breast cancer (MBC) (middle figure). Depressed women were significantly lower on wake + 30-minute cortisol levels. We have also included the mean cortisol response during baseline and TSST for depressed and nondepressed women who either have MBC or who were at risk for cardiovascular disease (50) to illustrate the relative hyporesponsiveness of the patients with MBC.

 

We conducted this TSST in collaboration with another study in our program project examining depression in men and women at risk for cardiovascular disease (CVD) (49) sharing exact protocols. For visual comparison, we present a figure in which depressed and nondepressed MBC and CVD females' cortisol responses to the TSST can be seen (Fig. 2).

Each of the results described remained significant after removing the nine women who were taking antidepressants but did not qualify for a current or lifetime diagnosis of depression.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
CONCLUSIONS
 NOTES
 REFERENCES
 
To our knowledge, this is the first analysis of endocrine, cardiovascular, autonomic, and hemodynamic stress response differences between depressed and nondepressed patients with MBC. Groups differed in HPA functioning in baseline cortisol waking rise, but we could not demonstrate differences in waking levels, diurnal slope, TSST response, or TSST recovery. However, depressed patients with MBC reported significantly more negative affect during the TSST (main effect throughout the TSST but no baseline difference) indicating that they responded more negatively to acute stress than the nondepressed. In other studies, depressed patients have reported blunted subjective emotional reactivity to stimuli like films with emotional content (e.g., (50)). Thus, the TSST was potent enough to overcome emotional blunting in our depressed group and so the lack of cortisol differences is likely not attributable to lack of emotional stress response. Both groups appear to have blunted HPA responses to the TSST (0.15–0.28 µg/dL compared with 0.10–0.50 in patients with primary breast cancer (21)), indicating that the HPA may be generally hyporesponsive for patients with MBC (51) as it has been shown to be with allostatic load (52) and PTSD (11). By comparison with females at risk for CVD (Fig. 2) (49), both MBC groups respond to the TSST at a level similar to the CVD depressed group. Lower overall cortisol secretion has been observed in teachers rated high on both stress and "burnout" coupled with low self-esteem and multiple somatic complaints (53), which would also characterize both MBC and depressed populations. The inability to mount a cortisol response to acute stress may both reflect the effects of chronic stress and compound the stress by limiting glucose mobilization necessary for response.

The depressed patients with MBC exhibited significantly attenuated baseline and TSST RSA (lnHF), a measure of parasympathetic functioning attenuated in other depressed samples (22,54,55). Although these women showed overall HPA blunting, their ANS appeared responsive to stress. RSA is related to ability to regulate emotions (56). Because emotion regulation skills can be successfully learned (57), RSA might be a good measure of the biologic impact of psychotherapy for depression (58–60).

In exploratory analyses, we found reductions for the depressed group in other heart rate variability (HRV) parameters at baseline (lnLF, lnVLF) and throughout the TSST (lnVLF). LnLF reflects both sympathetic and parasympathetic influences on the cardiovascular system and is strongly associated with blood pressure regulation. LnVLF, in addition to sympathetic and parasympathetic inputs, may be influenced by the thermoregulatory, peripheral vasomotor, and renin–angiotensin systems (61). HRV measures across all three frequency bands have been found to be reduced in depressed patients with CVD (17). In addition, depressed patients showed lower aortic impedance reactivity pointing to blunted sympathetic stress reactivity.

The principal suggestion from this study is the strong effect of depression on vagal attenuation in MBC survivors. Studies in healthy participants have related compromised parasympathetic functioning to greater stress vulnerability and lowered emotion regulatory capacity. The parasympathetic system is important for restoring homeostasis after stress and thus may be important in allostatic regulation. Vagal attenuation has been proposed as a pathophysiological link between depression and CVD risk (62). The current study indicates that depression is also associated with this ANS inflexibility in patients with MBC.

Depressed patients may have greater impairment across multiple physiological systems because of alterations in central nervous system regulation, e.g., in the central serotonergic system (63,64). Through descending pathways, this may alter subjective, immune, and autonomic function. This linkage may be the result of reduced flexibility in physiological responses as indexed by lower baseline RSA, less increase in RSA over the course of the TSST, or the pervasiveness of their negative affect.

Limitations
We assigned women to our depressed group based on meeting criteria for SCID diagnosis or their use of antidepressants. This method of assignment does not select for an extremely depressed (MDD) sample to compare with nondepressed as is the case in previous research in the general population. However, this sample more closely mirrors general levels of depression in patients with MBC who are actively coping with a threat to life. Levels of MBC depression that reach a diagnostic level are relatively rare, and yet the physiological impact of depression may still exist.

The significantly shorter disease-free intervals in the depressed group were statistically unrelated to outcomes. Additionally, there were fewer depressed nonwhites; however, there were too few nonwhites to examine statistical differences on outcomes reliably. Future studies may want to examine ethnic differences in these outcomes more thoroughly.

This was an observational study of depressed versus nondepressed patients with MBC. We cannot be certain what caused reduction in parasympathetic activity in the depressed group and so caution is warranted. Antidepressants are often given to women with MBC as they cope with the threat of death. Studies have found that some antidepressants may improve HRV (65), but our study found that the depressed group was significantly lower despite antidepressant use. Although it is known that older tricyclic antidepressants with pronounced anticholinergic side effects (66) may reduce parasympathetic activity, only three women in the HRV analyses were taking such medication.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
NOTES
 REFERENCES
 
A diagnosis of depression among patients with MBC may be associated with alterations in autonomic regulation at baseline as well as in reaction to mental stress. These results require independent confirmation, and future research could add stratification in recruitment for diagnosable clinical depression.

We thank Dirk Hellhammer, PhD, Seymour Levine, PhD, Rachel Yehuda, PhD, and Robert Sapolsky, PhD, for consultation regarding the interpretation of our cortisol results for this article; and Ben Varasteh and the General Clinical Research Center at Stanford for conducting cortisol assays. In addition, we thank project director Bita Nouriani, MS; research assistants Manijeh Parineh, Nausheen Ali, Allyson DeLorenzo, Julie Hall, and Suzanne Twirbutt; panel members for the TSST; and the women who participated.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
REFERENCES
 

Received for publication December 29, 2005; revision received May 4, 2006.

DOI:10.1097/01.psy.0000238216.88515.e5


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 CONCLUSIONS
 NOTES
 REFERENCES
 

  1. Omne-Ponten M, Holmberg L, Sjoden PO. Psychosocial adjustment among women with breast cancer stages I and II: six-year follow-up of consecutive patients. J Clin Oncol 1994;12:1778–82.[Abstract/Free Full Text]
  2. Kissane DW, Grabsch B, Love A, Clarke DM, Bloch S, Smith GC. Psychiatric disorder in women with early stage and advanced breast cancer: a comparative analysis. Aust N Z J Psychiatry 2004;38:320–6.[CrossRef][Medline]
  3. Derogatis LR, Morrow GR, Fetting J, Penman D, Piasetsky S, Schmale AM, Henrichs M, Carnicke CL Jr. The prevalence of psychiatric disorders among cancer patients. JAMA 1983;249:751–7.[Abstract]
  4. Burke HM, Davis MC, Ottec C, Mohr DC. Depression and cortisol responses to psychological stress: a meta-analysis. Psychoneuroendocrinology 2005;30:846–56.[CrossRef][Medline]
  5. McEwen BS. Protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann N Y Acad Sci 2004;1032:1–7.[CrossRef][Medline]
  6. Spiegel D, Giese-Davis J. Depression and cancer: mechanisms and disease progression. Biol Psychiatry 2003;54:269–82.[CrossRef][Medline]
  7. Giese-Davis J, Spiegel D. Emotional expression and cancer progression. In: Davidson RJ, Scherer KR, Hill Goldsmith H, eds. Handbook of Affective Sciences. Oxford: Oxford University Press; 2003:1053–82.
  8. Lopez JF, Akil H, Watson SJ. Neural circuits mediating stress. Biol Psychiatry 1999;46:1461–71.[CrossRef][Medline]
  9. Lupien SJ, Nair NP, Briere S, Maheu F, Tu MT, Lemay M, McEwen BS, Meaney MJ. Increased cortisol levels and impaired cognition in human aging: implication for depression and dementia in later life. Rev Neurosci 1999;10:117–39.[Medline]
  10. Raison CL, Miller AH. The neuroimmunology of stress and depression. Semin Clin Neuropsychiatry 2001;6:277–94.[CrossRef][Medline]
  11. Yehuda R, Teicher MH, Trestman RL, Levengood RA, Siever LJ. Cortisol regulation in posttraumatic stress disorder and major depression: a chronobiological analysis. Biol Psychiatry 1996;40:79–88.[CrossRef][Medline]
  12. Sephton S, Sapolsky R, Kraemer H, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 2000;92:994–1000.[Abstract/Free Full Text]
  13. Holsboer F. Stress, hypercortisolism and corticosteroid receptors in depression: implications for therapy. J Affect Disord 2001;62:77–91.[CrossRef][Medline]
  14. Ito T, Saitoh D, Takasu A, Kiyozmi T, Sakamoto T, Okada Y. Serum cortisol as predictive marker of the outcome in patients resuscitated after cardiopulmonary arrest. Resuscitation 2004;62:55–60.[CrossRef][Medline]
  15. Balogh S, Fitzpatrick DF, Hendricks SE, Paige SR. Increases in heart rate variability with successful treatment in patients with major depressive disorder. Psychopharmacol Bull 1993;29:201–6.[Medline]
  16. Dalack GW, Roose SP. Perspectives on the relationship between cardiovascular disease and affective disorder. J Clin Psychiatry 1990;51(Suppl):4–9; discussion 10–1.
  17. Carney R, Blumenthal J, Stein P, Watkins L, Catellier D, Berkman L, Czajkowski S, O'Connor C, Stone P, Freedland K. Depression, heart rate variability, and acute myocardial infarction. Circulation 2001;104:2024–8.[Abstract/Free Full Text]
  18. Miller GE, Rohleder N, Stetler C, Kirschbaum C. Clinical depression and regulation of the inflammatory response during acute stress. Psychosom Med 2005;67:679–87.[Abstract/Free Full Text]
  19. Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 2002;64:604–11.[Abstract/Free Full Text]
  20. Bower JE, Ganz PA, Aziz N, Fahey JL, Cole SW. T-cell homeostasis in breast cancer survivors with persistent fatigue. J Natl Cancer Inst 2003;95:1165–8.[Abstract/Free Full Text]
  21. Bower JE, Ganz PA, Aziz N. Altered cortisol response to psychologic stress in breast cancer survivors with persistent fatigue. Psychosom Med 2005;67:277–80.[Abstract/Free Full Text]
  22. Rottenberg J. Cardiac vagal tone in depression: a critical analysis. Biol Psychol. In press.
  23. Kibler JL, Ma M. Depressive symptoms and cardiovascular reactivity to laboratory behavioral stress. Int J Behav Med 2004;11:81–7.[CrossRef][Medline]
  24. Cacioppo JT, Berntson GG, Binkley PF, Quigley KS, Uchino BN, Fieldstone A. Autonomic cardiac control. II. Noninvasive indices and basal response as revealed by autonomic blockades. Psychophysiology 1994;31:586–98.[Medline]
  25. Berntson GG, Bigger JT Jr, Eckberg DL, Grossman P, Kaufmann PG, Malik M, Nagaraja HN, Porges SW, Saul JP, Stone PH, van der Molen MW. Heart rate variability: origins, methods, and interpretive caveats. Psychophysiology 1997;34:623–48.[Medline]
  26. Raison CL, Miller AH. When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry 2003;160:1554–65.[Abstract/Free Full Text]
  27. Porter RJ, Gallagher P, Watson S, Young AH. Corticosteroid–serotonin interactions in depression: a review of the human evidence. Psychopharmacology (Berl) 2004;173:1–17.[CrossRef][Medline]
  28. Posener JA, DeBattista C, Williams GH, Kraemer HC, Kalehzan BM, Schatzberg AF. 24-Hour monitoring of cortisol and corticotropin secretion in psychotic and nonpsychotic major depression. Arch Gen Psychiatry 2000;57:755–60.[Abstract/Free Full Text]
  29. Posener JA, Charles D, Veldhuis JD, Province MA, Williams GH, Schatzberg AF. Process irregularity of cortisol and adrenocorticotropin secretion in men with major depressive disorder. Psychoneuroendocrinology 2004;29:1129–37.[CrossRef][Medline]
  30. Burke HM, Fernald LC, Gertler PJ, Adler NE. Depressive symptoms are associated with blunted cortisol stress responses in very low-income women. Psychosom Med 2005;67:211–6.[Abstract/Free Full Text]
  31. Ravindran AV, Griffiths J, Merali Z, Anisman H. Primary dysthymia: a study of several psychosocial, endocrine and immune correlates. J Affect Disord 1996;40:73–84.[CrossRef][Medline]
  32. Kirschbaum C, Pirke KM, Hellhammer DH. The ‘Trier Social Stress Test’—a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 1993;28:76–81.[Medline]
  33. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured Clinical Interview for DSM-IV axis I disorders. Washington, DC: American Psychiatric Press; 1995.
  34. Beck AT, Beamesderfer A. Assessment of depression: the depression inventory. Mod Probl Pharmacopsychiatry 1974;7:151–69.[Medline]
  35. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983;24:385–96.[CrossRef][Medline]
  36. Ware JE Jr. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. J Consult Clin Psychol 1992;60:213–9.[CrossRef][Medline]
  37. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54:1063–70.[CrossRef][Medline]
  38. Epel ES, McEwen B, Seeman T, Matthews K, Castellazzo G, Brownell KD, Bell J, Ickovics JR. Stress and body shape: stress-induced cortisol secretion is consistently greater among women with central fat. Psychosom Med 2000;62:623–32.[Abstract/Free Full Text]
  39. Dickerson SS, Kemeny ME. Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research. Psychol Bull 2004;130:355–91.[CrossRef][Medline]
  40. Dressendorfer RA, Kirschbaum C, Rohde W, Stahl F, Strasburger CJ. Synthesis of a cortisol–biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. J Steroid Biochem Mol Biol 1992;43:683–92.[CrossRef][Medline]
  41. Sherwood A, Allen MT, Fahrenberg J, Kelsey RM, Lovallo WR, van Doornen LJ. Methodological guidelines for impedance cardiography. Psychophysiology 1990;27:1–23.[Medline]
  42. Wilhelm FH, Grossman P, Roth WT. Analysis of cardiovascular regulation. Biomed Sci Instrum 1999;35:135–40.[Medline]
  43. Stok WJ, Baisch F, Hillebrecht A, Schulz H, Meyer M, Karemaker J. Noninvasive cardiac output measurement by arterial pulse analysis compared with inert gas rebreathing. J Appl Physiol 1993;74:2687–93.[Abstract/Free Full Text]
  44. Resnick LM, Militianu D, Cunnings AJ, Pipe JG, Evelhoch JL, Soulen RL, Lester MA. Pulse waveform analysis of arterial compliance: relation to other techniques, age, and metabolic variables. Am J Hypertens 2000;13:1243–9.[CrossRef][Medline]
  45. Saul JP, Berger RD, Albrecht P, Stein SP, Chen MH, Cohen RJ. Transfer function analysis of the circulation: unique insights into cardiovascular regulation. Am J Physiol 1991;261:H1231–45.
  46. Robbe HW, Mulder LJ, Ruddel H, Langewitz WA, Veldman JB, Mulder G. Assessment of baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 1987;10:538–43.[Abstract/Free Full Text]
  47. Bagiella E, Sloan RP, Heitjan DF. Mixed-effects models in psychophysiology. Psychophysiology 2000;37:13–20.[CrossRef][Medline]
  48. Hsu LM. Biases of success rate differences shown in binomial effect size displays. Psychol Bull 2004;9:183–97.
  49. Taylor CB, Conrad A, Wilhelm FW, Neri E, DeLorenzo A, Kramer MA, Giese-Davis J, Roth WT, Oka R, Cooke JP, Kraemer HC, Spiegel D. Psychophysiological and cortisol responses to psychological stress in depressed and non-depressed older men and women with elevated CVD risk. Psychosom Med 2006;68:538–46.[Abstract/Free Full Text]
  50. Rottenberg J, Wilhelm FH, Gross JJ, Gotlib IH. Vagal rebound during resolution of tearful crying among depressed and nondepressed individuals. Psychophysiology 2003;40:1–6.[CrossRef][Medline]
  51. Abercrombie HC, Giese-Davis J, Sephton S, Epel ES, Turner-Cobb JM, Spiegel D. Flattened cortisol rhythms in metastatic breast cancer patients. Psychoneuroendocrinology 2004;29:1082–92.[CrossRef][Medline]
  52. McEwen BS. Protective and damaging effects of stress mediators. N Engl J Med 1998;338:171–9.[Free Full Text]
  53. Pruessner JC, Hellhammer DH, Kirschbaum C. Burnout, perceived stress, and cortisol responses to awakening. Psychosom Med 1999;61:197–204.[Abstract/Free Full Text]
  54. Hughes JW, Stoney CM. Depressed mood is related to high-frequency heart rate variability during stressors. Psychosom Med 2000;62:796–803.[Abstract/Free Full Text]
  55. Guinjoan SM, de Guevara MSL, Correa C, Schauffele SI, Nicola-Siri L, Fahrer RD, Ortiz-Fragola E, Martinez-Martinez JA, Cardinali DP. Cardiac parasympathetic dysfunction related to depression in older adults with acute coronary syndromes. J Psychosom Res 2004;56:83–8.[CrossRef][Medline]
  56. Porges SW. Cardiac vagal tone: a physiological index of stress. Neurosci Biobehav Rev 1995;19:225–33.[CrossRef][Medline]
  57. Giese-Davis J, Koopman C, Butler L, Classen C, Cordova M, Fobair P, Benson J, Kraemer H, Spiegel D. Change in emotion-regulation strategy for women with metastatic breast cancer following supportive–expressive group therapy. J Consult Clin Psychol 2002;70:916–25.[CrossRef][Medline]
  58. Chambers AS, Allen JJB. Vagal tone as an indicator of treatment response in major depression. Psychophysiology 2002;39:861–4.[CrossRef][Medline]
  59. Carney RM, Freedland KE, Stein PK, Skala JA, Hoffman P, Jaffe AS. Change in heart rate and heart rate variability during treatment for depression in patients with coronary heart disease. Psychosom Med 2000;62:639–47.[Abstract/Free Full Text]
  60. Khaykin Y, Dorian P, Baker B, Shapiro C, Sandor P, Mironov D, Irvine J, Newman O. Autonomic correlates of antidepressant treatment using heart-rate variability analysis. Can J Psychiatry 1998;43:183–6.[Medline]
  61. Kamath M, Ghista D, Fallen E, Fitchett D, Miller D, McKelvie R. Heart rate variability power spectrogram as a potential noninvasive signature of cardiac regulatory system response, mechanisms, and disorders. Heart Vessels 1987;3:33–41.[CrossRef][Medline]
  62. Rozanski A, Blumenthal J, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999;99:2192–217.[Abstract/Free Full Text]
  63. Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety 2000;12(Suppl):2–19.
  64. Siever LJ, Davis KL. Overview: toward a dysregulation hypothesis of depression. Am J Psychiatry 1985;142:1017–31.[Abstract/Free Full Text]
  65. Phebe T, Adamson P, Miranda RJ, Scarborough A, Williams D, Groff J, McClean H. Paroxetine increases heart rate variability in panic disorder. J Clin Psychopharmacol 1997;17:370–6.[CrossRef][Medline]
  66. Pezzella G, Moslinger-Gehmayr R, Contu A. Treatment of depression in patients with breast cancer: a comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 2001;70:1–10.[CrossRef][Medline]



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