Background: Depression and ischemic heart disease (IHD) are associated with persistent stress and autonomic nervous system (ANS) dysfunction. The former can be measured by pressure pain sensitivity (PPS) of the sternum, and the latter by the PPS and systolic blood pressure (SBP) response to a tilt table test (TTT). Beta-blocker treatment reduces the efferent beta-adrenergic ANS function, and thus, the physiological stress response. Objective: To test the effect of beta-blockers on changes in depression score in patients with IHD, as well as the influence on persistent stress and ANS dysfunction. Methods: Three months of non-pharmacological intervention aiming at reducing PPS and depression score in patients with stable IHD. Beta-blocker users (N = 102) were compared with non-users (N = 75), with respect to signs of depression measured by the Major Depressive Inventory questionnaire (MDI), resting PPS, and PPS and SBP response to TTT. Results: MDI score decreased 30% in non-users (p = 0.005) compared to 4% (p > 0.1) among users (between-group p = 0.003; effect size = 0.4). Resting PPS decreased in both the groups. Among most vulnerable patients with MDI ≥ 15, reductions in MDI score and resting PPS score correlated in non-users, only (r = 0.69, p = 0.007). Reduction in resting PPS correlated with an increase in PPS and SBP response to TTT. Conclusions: Stress intervention in patients with IHD was anti-depressive in non-users, only. Similarly, the association between the reduction in depression, reduction in persistent stress, and restoration of ANS dysfunction was only seen in non-users, suggesting a central role of beta-adrenergic receptors in the association between these factors.
Depressive disorders and ischemic heart disease (IHD) are both considered as the leading causes of the global burden of disease [
Increased pressure pain sensitivity of the sternum (PPS) has been observed in patients with stable IHD [
ANSD is associated with increased risk of morbidity and mortality in case of heart diseases independently of traditional risk factors [
Objectives: The present study was performed in order to explore the interactions between depression, persistent stress, and ANSD in IHD patients with or without treatment with beta-adrenergic blocking medication. The study focused on the functioning of beta-adrenergic receptors in modulating these associations. This was done as a post-hoc analysis of a large stress intervention trial, testing the anti-depressive effect of reducing the level of persistent stress by non-pharmacological means in patients with stable IHD. These patients were divided into beta-adrenergic receptor blockade medication users or non-users.
The participants were part of a larger study group (N = 213) participating in a prospective randomized intervention trial [
Since both the active and control groups experienced a significant reduction in PPS during the intervention period, and the intervention was non-pharmacological in nature, the groups were combined into one group for the purpose of the present study, and then further divided into groups of non-users (N = 75) and users (N = 106) of beta-blockade medication. Among the users of beta-blockade medication, four used hydrophilic beta-blockers
(e.g., Atenolol), which fails to penetrate the blood-brain barrier, and the remaining 102 used lipophilic beta- blockers that possess the penetrative property. To exclude bias from this difference, the Atenolol users were excluded from the study.
Informed consent was obtained from all the participants after providing oral and written information about the study. The study was conducted at Herlev University hospital, Copenhagen, and was approved by the local ethics committee (ID H-4-2010-135), and registered on www.clinicaltrials.gov (NCT01513824).
The stress reduction interventional program was carried out for a three months period, and has previously been reported in detail [
The Major Depressive Inventory (MDI) questionnaire [
The variables were recorded before and after three months of non-pharmacological intervention period with the aim to reduce elevated resting PPS. This was performed as a randomized prospective trial that has been previously described in detail [
In order to evaluate the potential influence of the beta-blockade treatment, the observed changes in effect variables during the three months of intervention for non-users and users were compared. In addition the internal correlations between the changes in the effect variables were compared. The degree of ANSD was measured by the PPS and SBP response due to TTT. However, owing to the very nature of beta-blockade medication, any secondary effect on the SBP response to TTT from a non-medical induced reduction in sympathetic tone would be expected to be blunted by the beta-blockers.
An algometric instrument (Ull Meter: UllCare Ltd. Lemchesvej 1, DK 2900 Hellerup, Denmark) (Patent No. EP 1750772 B1) was used for measurement of the Pressure Pain Sensitivity of the sternum (PPS) [
This test induces a transient increase in the sympathetic tone and is usually conducted for diagnostics with respect to adrenergic ANS function [
To minimize bias, the following precautions were taken: 1) the PPS device was designed in a manner that made the measurement non-visible to both the instructor and patient until the end of each measurement; 2) the professional instructor measuring PPS and conducting the TTT was blinded to the results of randomization; and 3) before randomization the patients were instructed not to discuss the result of randomization with the research personnel performing the follow-up recordings after the three-month period.
In the original and approved protocol, sample size was calculated based on an anticipated anti-depressive effect size of 0.4, alpha of 0.05 and beta of 0.20 which corresponded to a sample size of 300.
Non-parametrical statistics were used for group comparison, Wilcoxon two-sample test for between-group analysis, Mann-Whitney one-sample test for with-in the group analysis, and the parametric Pearson’s test for correlation analysis. For testing of statistical significance, all randomized patients who concluded the second set of measurements were included. The effect size for depression score was calculated as the difference in mean depression score before and after the intervention for the two groups divided by the standard deviation of the depression score for both groups [
Due to the nature of the intervention, an effect on the depression score may be minor or absent if it is within the normal range at baseline. This issue has previously been discussed in a comprehensive manner [
The demographics of the enrolled patients are given in
Depression: Changes in the depression score differed between the groups: In non-users MDI decreased by 30% (p = 0.005) as compared to a non-significant reduction of 4% in the user group (between the groups p = 0.003). The anti-depressive effect size was 0.4 for non-users when compared to the users.
In the subgroup of patients with a raised MDI ≥ 15 (N = 33), which is indicative of incipient depression, MDI score in non-users (N = 17) decreased from mean 20.0 (SD: 5.5) before the intervention to 10.9 (SD: 6.9) after intervention (p = 0.001), whereas users (N = 16) only demonstrated a non-significant change, from mean 19.6 to 17.8 after the intervention (p > 0.1) (between the groups p = 0.009). In this subgroup of patients, the anti-de- pressive effect size was 0.9 for the non-users when compared to users.
Persistent stress: Resting PPS was reduced for the total group (N = 177) by a mean of 12 arbitrary units (SD: 21), equal to approximately 15% (p < 0.0001). The reduction was independent of the use of beta-blockers, and was similar in both the groups (between the groups p > 0.1).
ANS dysfunction: The PPS response to a TTT increased by an average of three arbitrary units (SD: 18), equal
−Beta-blockade | +Beta-blockade | |
---|---|---|
N | 75 | 102 |
Male, % | 66 | 78* |
Age in years, mean (SD) | 62 (9) | 63 (7) |
Resting PPS, (arbitrary units), mean (SD) | 76.6 (13.0) | 78.3 (13.0) |
MDI, (arbitrary units), mean (SD) | 9.4 (6.8) | 8.6 (7.5) |
PPS response to TTT, (arbitrary units), mean (SD) | −5.4 (11.6) | −4.7 (14.2) |
Systolic blood pressure (SBP) response to TTT, (mmHg), mean (SD) | −3.3 (13.1) | −2.3 (12.3) |
Cardiac variables | ||
Previous myocardial infarction (%) | 63 | 68 |
Treated with PCI (%) | 64 | 73 |
Treated with CABG (%) | 23 | 31 |
Resting pulse, (beats/min), mean (SD) | 64 (11) | 59 (9)** |
SBP, (mmHg), mean (SD) | 134 (16) | 1330 (17) |
Diastolic blood pressure, (mmHg), mean (SD) | 789(9) | 80 (9) |
Cardiac risk factors | ||
Body Mass Index, (kg/m2), mean (SD) | 27.4 (4.8) | 27.6 (4) |
Triglyceride, (mmol/l), mean (SD) | 1.3 (0.8) | 1.5 (0.9) |
Total Cholesterol, (mmol/l), mean (SD) | 4.4 (1.0) | 4.3 (1.0) |
HDL Cholesterol, (mmol/l), mean (SD) | 1.3 (0.4) | 1.2 (0.4) |
LDL Cholesterol, (mmol/l), mean (SD) | 2.5 (0.8) | 2.3 (0.8) |
Current smoker (%) | 2 | 2 |
Self-reported co-morbidity | ||
Heart failure (%) | 19 | 44*** |
Chronic obstructive lung disease (%) | 5 | 9 |
Diabetes (%) | 12 | 15 |
Previous stroke (%) | 6 | 8 |
Previous treatment for depression (%) | 16 | 14 |
Medication | ||
Cholesterol-lowering medication (%) | 85 | 96 |
Calcium antagonists (%) | 19 | 25 |
Angiotensin-II antagonist and/or ACE inhibitors (%) | 51 | 59 |
Diuretics (thiazide or furosemide) (%) | 33 | 35 |
For between-group significance: *p < 0.05; **p < 0.001; ***p < 0.0001.
to approximately 55% (p < 0.03) with no difference between the non-users and users of beta-blocking agents. However, the SBP response to TTT remained unaltered (mean increase of 1 mmHg (SD: 18)), with no significant difference between the two groups (between the groups p > 0.1).
Depression versus persistent stress: No significant associations were found between the changes in MDI score
Variable | Number total N (number of Non-users/users) | −Beta-blockade | +Beta-blockade | Significance p value (between-group) |
---|---|---|---|---|
Change during three months of intervention | ||||
MDI, mean (SD) | 177 (75/102) | −2.8 (5.2)* | −0.4 (4.1) | p = 0.003 |
MDI, mean (SD) for patients with MDI ≥ 15 at baseline | 33 (17/16) | −9.1 (6.5)* | −1.8 (6.2) | p = 0.009 |
Resting PPS, mean (SD) | 177 (75/102) | −10 (17)* | −14 (24)* | n.s |
PPS response to TTT, mean (SD) | 177 (75/102) | 3.0 (16) | 2.8 (19) | n.s |
SBP response to TTT , mean (SD) | 177 (75/102) | 2.4 mmHg | 0.7 mmHg | n.s. |
Correlations between changes during 3 months of intervention | ||||
Change in MDI score versus change in resting PPS | 177 (75/102) | −0.09 | −0.08 | n.s |
Change in MDI score versus change resting PPS for patients with MDI ≥15 at baseline | 33 (17/16) | −0.69* | −0.04 | p = 0.05 |
Change in MDI score versus change in PPS response to TTT | 177 (75/102) | −0.02 | 0.37* | p = 0.02 |
Change in MDI score versus change in PPS response to TTT for patients with MDI ≥ 15 at baseline | 33 (17/16) | −0.43 | 0.54* | p = 0.02 |
Change in resting PPS versus change in PPS response to TTT | 177 (75/102) | 0.37* | 0.59* | n.s |
Change in resting PPS versus change in SBP response to TTT | 177 (75/102) | 0.32* | + 0.13 | P = 0.004 |
For between-group significance: Exact “p” value is presented; n.s. = non significant. For within group significance: *= p < 0.05.
and resting PPS, neither in the total group nor in the two subgroups of beta-blocker users and non-users. In contrast to the total groups of patients, the reductions in MDI score in the subgroup of patients with MDI ≥ 15 (N = 33) were significantly associated with reductions in resting PPS in the non-user group (r = 0.69, intra-group p = 0.007), but not in the user group (r = 0.04, p > 0.1) (between the groups p = 0.05).
Depression versus ANSD: Looking at the total group (N = 177), the reduction in MDI during the three months of intervention was associated with a reduction in the PPS response to a TTT (r = 0.19; p = 0.02). This positive correlation was driven only by the beta-blocker users with a significant and positive association (r = 0.37) while no correlation was found in the non-user group (r = 0.02) (p > 0.01). Considering the most depressed patients, the subgroup of the patient having MDI ≥ 15, the beta-blocker users demonstrated an even stronger positive association between the reductions in MDI and PPS responses to a TTT (r = 0.54, p = 0.04). In contrast, this association now was negative with regard to the non-users (r = −0.43, p > 0.1) (between the groups p = 0.02) (
Persistent stress versus ANSD: Reductions over three months in resting PPS were associated with an increase in the PPS response to TTT both in the total group (r = −0.50, p < 0.0001) (N = 177) (
In patients with IHD, the non-users of adrenergic beta-receptor blockade medication showed a clinically relevant anti-depressive effect from a three months non-pharmacological intervention program. This was not the case among the beta-blocker users. In the subgroup of patients with an elevated depression score (MDI score ≥ 15), the difference was even more pronounced. Statistically significant between-group differences were found between the non-users and users with respect to the correlations between the changes in depression score versus the changes in resting PPS as the measure of persistent stress. The same between-group differences were found between the changes in depression score and the changes in the PPS response to TTT as the measure of ANS function. Furthermore, the reduction in resting PPS was significantly associated with an increase in SBP response to TTT only in case of the non-users, with a significant difference to the user group.
Virtually in the group of non-users, there was a decrease in the levels of perceived depression (i.e., a decrease in the MDI score) and persistent stress (i.e., a decrease in resting PPS), with partial restoration of ANSD (i.e., an increase in the PPS and SBP response to TTT).
In contrast, users demonstrated a different pattern in which no reduction was observed in the perceived level of depression. However, the level of persistent stress was reduced, and the ANSD was restored as measured by the PPS response to a TTT. When measuring the ANS function by the means of SBP response to TTT, no restoration of ANSD was obtained.
These overall findings suggested that the level of persistent stress was reduced in the case of the non-users, and this reduction was associated with restoration of ANSD, which probably led to the further reduction of the perceived level of depression. However, the reduction in the level of persistent stress remained stable in case of the users, but the beneficial effect on the perceived level of depression disappeared. Also, while measuring the restoration of ANSD, the present findings demonstrated a potential distortion between the PPS and SBP response to TTT. Thus, the change over time in the PPS response to TTT remained similar for both the users and non-users, whereas the association between the reduction in resting PPS and change in SBP response to TTT vanished among the users. Accordingly, the present data might suggest that the beta blockage medication inhibits the efferent effects of the reduction of an elevated PPS measure at the level of transmission at the beta-rec- eptor, and thus, the effect of ANSD restoration on the SBP response to TTT and depression reduction. Consequently, the regulation of resting PPS and PPS response to TTT seems to be superior in the ANS hierarchy than the SBP response to TTT and the individually perceived level of depression, both of which seems to be inferiorly located to the beta-receptor in the ANS hierarchy. These speculations obviously call for further studies.
It is known that the beta blocker treatment may induce depression as one of its side effects [
The demonstrated positive association between the reduction in depression score during the three months of intervention and a similar reduction in the PPS response to TTT was counter-intuitive but was only found among the beta-blocker users. Such an association might simply be due to the fact that beta-blocker treatment abolished the effect on depression score when resting PPS was reduced, and thus, distorted the association. In the subgroup of patients with an elevated MDI score, the reduction over time was associated with an increase in the PPS response to TTT, and thus, to a lesser degree of ANSD. This is another clue to the suggestion that the beta-adrenergic receptors are engaged in the association between the ANS function and depression. It also might be an argument for the fact that the anti-depressive effect from alleviation of ANS dysfunction and concomitant reduction of an elevated level of persistent stress in IHD patients is mediated by the beta-adrenergic receptor.
Our findings suggest an internal association between the persistent stress, depression, and ANS dysfunction in patients with stable IHD. When an elevated level of persistent stress was reduced by non-pharmaceutical means, the use of beta-blockers had an inhibiting effect on the concomitant reduction in depression score. In addition, the use of beta-blockers was similarly found to inhibit the associations between the alleviation of ANS dysfunction and reduction of the depression score. This latter association was significantly stronger than the association between the reductions in the level of persistent stress and depression score. The use of beta-blockers did not influence the reduction of persistent stress, the restoration of ANS dysfunction or the association between the two. Accordingly, the present findings may suggest that the association between depression and stress is indirect, with ANS as the intermediate link.
The present findings are in line with others suggesting ANS to be an important link between depression and persistent stress [
The strengths of the study were: i) the large number of persons studied, ii) the use of a well established experimental procedure with a fully controllable stimulation of ANS, and iii) the previously tested PPS discrimination point for an elevated level of persistent stress [
It should also be underlined that with respect to the possible influence of beta-blockers on PPS measure, the study was a hypothesis confirming study, based on our previous observation as mentioned in the introduction. However, with respect to the possible influence from beta-blockade medication on depression, the study is hypothesis generating, only. In order to study an association that includes a reduction of the depression score, the reduction may be minor or absent if the depression score is within normal range at baseline. This has already been discussed in a comprehensive manner [
With respect to a possible clinical relevance of the achieved anti-depressive effects in the non-user group the effect size was 0.4 for the group as a whole with a mean MDI depression score of 9.4 at baseline, whereas the effect size was 0.9 among the subgroup of patients with a score ≥ 15 at baseline. This may be compared to the minimum clinical relevant antidepressant effect for pharmacological treatment of patients with overt depression (e.g. MDI score ≥ 20 at baseline) which was 0.3 according to the US Federal Drug Administration [
The future studies based on the present findings might accommodate the fact regarding the existence of beta-adrenergic receptors in the brain at a location at which an improved ANS function may exercise an anti- depressive effect. Although a confirmation of the existence of beta-adrenergic receptors in the brain has proven to be unusually difficult, it seems likely that such receptors are located in the brain [
Little is known about stress resilience, for e.g., when and how stress shifts from being beneficial and protective to becoming deleterious [
In conclusion, the study suggests that the beta-adrenergic receptor represents a new and clinically relevant key to the understanding of the association between depression, persistent stress, and ANS dysfunction in IHD.
We are thankful to the staff of the Metabolic Ward for their contribution to the study: Helle-Marina Oxfeldt and Tine Skogen-Lassen. We also thank the staff at the Rehabilitation Unit at Department of Cardiology, Gentofte University Hospital, Copenhagen, Denmark for providing us with their database on patients with IHD, who had completed cardiac rehabilitation. We thank professorMD, DMSciNiels H. Secher, Department of Anaesthesiology, Rigshospitalet, Denmark for critical review of the manuscript.
This work was supported by the Johan Schrøder’s Family and Business Foundation. Natasha Bergmann holds a pre-graduate scholarship sponsored by the Lundbeck Foundation.
Søren Ballegaard invented the PPS instrument used to measure PPS. He is also a shareholder of the company that owns the patents associated with the PPS instrument. To avoid bias, he was not involved in the patient contact, collection of data, or statistical analysis. As such he had no access to the study site (Herlev Hospital) during the entire study period. No other disclosures were reported.
Søren Ballegaard,Natasha Bergmann,Benny Karpatschof,Jesper Kristiansen,Finn Gyntelberg,Lars Arendt-Nielsen,Per Bech,Åke Hjalmarson,Jens Faber, (2016) Association between Depression, Pressure Pain Sensitivity, Stress and Autonomous Nervous System Function in Stable Ischemic Heart Disease: Impact of Beta-Adrenergic Receptor Blockade. Journal of Behavioral and Brain Science,06,317-328. doi: 10.4236/jbbs.2016.68031