INT’L. J. PSYCHIATRY IN MEDICINE, Vol. 47(2) 115-129, 2014
OUTCOME OF TREATMENT WITH ANTIDEPRESSANTS IN PATIENTS WITH HYPERTENSION AND UNDETECTED DEPRESSION
INES DIMINIC-LISICA BRANISLAVA POPOVIC University of Rijeka, Croatia JELENA REBIC KBC Rijeka, Croatia MIRO KLARIC Mostar Clinical Hospital, Bosnia and Herzegovina TANJA FRANCIŠKOVIC University of Rijeka, Croatia
ABSTRACT
Objective: The objective of the research was to determine whether the administration of antidepressants, concurrently with antihypertensive therapy, leads to the better regulation of blood pressure in patients with hypertension and increased depressiveness. Methods: Research was conducted in two outpatient family clinics in Rijeka, Croatia, on 452 patients with arterial hypertension who had not been diagnosed with depression prior to the study. The diagnosis of hypertension was made in accordance with the European Society of Hypertension and the European Society of Cardiology Guidelines for the Management of Arterial Hypertension. Using the Beck Depression Inventory and the ICD-10 criteria for depression, a group of depressed hypertensive patients (N = 134) was selected. Out of a total of 134 selected patients, 73 patients (N = 73) were receiving antidepressants together with antihypertensives for 24 weeks. They formed the experimental group. The rest of the patients (N = 61) continued to receive only antihypertensives and 115 Ó 2014, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.47.2.c http://baywood.com
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they formed the control group. Results: After the end of the 24-week therapy, the experimental group of patients had significantly lower levels of both systolic and diastolic blood pressure (Z = 7.42; P < 0.001; and Z = 7.36; P < 0.001). The control group saw no significant difference between the level of blood pressure (both systolic and diastolic) prior to and after this period. Conclusion: The application of antidepressant therapy in patients with hypertension who are also depressed may be associated with the better control of blood pressure, which reduces the risk of cardiovascular disease in addition to alleviating depressive symptoms. (Int’l. J. Psychiatry in Medicine 2014;47:115-129)
Key Words: antidepressants, hypertension, undetected depression, blood pressure regulation
INTRODUCTION Depression and hypertension are highly prevalent diseases in the modern world [1-3]. A substantial literature supports clinically important associations between psychiatric illness and chronic medical conditions [4]. An increase in the prevalence of hypertension, as well as insufficient regulation of blood pressure and a concomitant of premature mortality from cardiovascular disease, require more extensive research into risk factors and aspects of the prevalence of these illnesses [5-8]. Depressive disorders are prevalent among the medically ill and it is known that depressive disorder can negatively affect the course of physical illness [9, 10]. Numerous studies suggest an association between increased cardiovascular mortality, heart failure, and high blood pressure with depression [11-16]. The presence of co-morbid illnesses, such as depression, can be one of the causes of the inadequate regulation of blood pressure. The link between two very common illnesses among the population—hypertension and depression—has not yet been adequately examined. A considerable number of recent studies deal with the joint neurophysiological mechanisms as well as the joint genetic risk factors of hypertension and depression [17-22]. Depressive symptoms may be an important modifiable barrier to antihypertensive medication adherence in older adults [23]. Co-morbid depression in somatic patients often passes unnoticed and remains untreated [3, 24]. This fact is not sufficiently taken into account in daily practice. However, we should consider that treating depression with antidepressants leads to a reduction of depression symptoms and decreases blood pressure levels [25]. Cooperation between primary care and psychiatric services significantly helps with results [26]. The purpose of this study was to determine whether, among patients with essential hypertension, there are those who suffer from unrecognized depressive symptoms, and whether using antidepressants concurrently with antihypertensive drugs leads to the better control of blood pressure.
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METHODS The research was conducted from February to December 2009 in two outpatient family medicine clinics caring for 2,550 persons in Rijeka, Croatia. Participants The study included patients with chronic arterial hypertension. Of 595 registered patients with arterial hypertension, 72 (12.10%) were unavailable due to the temporary absence from their place of residence or as a result of the irregular attendance of routine checkups and 16 (2.68%) patients refused to participate in the study. The study excluded 10 (1.68%) patients with severe physical illnesses and general disability, as well as 14 (2.35%) patients with secondary hypertension and 31 (5.21%) patients with a history of mental disorders. Thus, the study included 452 patients (or 75.96%) of registered hypertensive patients. All the patients involved in the study were adults, aged 23-90 years. The patients were informed of the research and they gave their written informed consent. Data from medical records and data obtained by questionnaires were presented anonymously and the patients’ identities were protected. The study was approved by the Ethics Committee School of Medicine, University of Rijeka. Procedures Arterial hypertension diagnosis was established according to ESH/ESC guidelines [27] or based on the criteria of being treated with antihypertensives. The patients were included in accordance with their order of arrival at the clinic for a routine check-up or the continuation of therapy. In order to determine general demographic data, the subjects responded to a specially-designed, general questionnaire. The general questionnaire contained demographic questions referring to participants in general as well as questions referring to co-morbid chronic illnesses and medication therapies. Information on chronic illness and medication therapies was checked in the subjects’ medical records. In order to identify depression levels, the Beck Depression Inventory [28, 29] was used. The Beck Depression Inventory (BDI) is a self-evaluation instrument consisting of 21 items. The scores range from 0 to 63. The standard cutoffs are as follows: 0–9 indicates non-depressed, 10-18 indicates mildly-moderately depressed, 19-29 indicates moderately-severely depressed, and 30–63 indicates severely depressed [28, 29]. In this study, we defined a cutoff >16 because of the higher sensitivity and specificity of the test and greater clinical relevance ([30, 31]. Based on the BDI, the subjects were divided into two groups: the non-depressed group, which also included mildly depressed subjects (BDI £ 16), and a group of depressed patients, which included mildly depressed subjects with (BDI > 16) moderately and severely depressed.
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Among a group of depressed patients, researchers (family physicians) confirmed depression by the ICD-10 criteria for depression, and it was supervised by a psychiatrist. All the patients met the criteria for a depressive episode-type major depression that lasted longer than 2 weeks. The researchers compared the blood pressure levels between the groups. During the research, all the patients with BDI scores higher than 16 were monitored over a period of 24 weeks. This group consisted of 134 patients. These patients had a depressive disorder that was not detected prior to the research. These patients were recommended antidepressants together with antihypertensives. Out of a total of 134 patients with arterial hypertension and depression, only 73 began and continued receiving antidepressants with antihypertensives for 24 weeks. They formed the experimental group. Out of a total of 134 hypertensive patients with depression, 61 did not receive antidepressants for a variety of reasons. These patients did not receive any other treatment, such as psychotherapy, unless with the support of family physicians at every visit. They formed the control group. Of 61 such patients, 29 patients rejected antidepressants, offering many explanations (“I’m taking too many drugs,” “I’ll think about it,” etc.), 19 patients started taking antidepressants, but failed to cooperate and terminated their therapy, and seven patients ended their treatment due to drug intolerance or side-effects. This group also included six patients who stopped using antidepressants because of the independent occurrence of various health problems and the use of hospital health services. At the beginning and the end of the research, the subjects’ blood pressures were measured three times a fortnight. The mean values of their blood pressures were calculated afterwards. Blood pressure was taken by using a mercury sphygmomanometer with appropriate cuffs, after the patients had been sitting relaxed for at least 5 minutes. Blood pressure was taken once every 4 weeks throughout the research among both groups. In the first month of taking antidepressants, the experimental group had regular checkups after the 7th, 14th, and 28th day of their antidepressant therapy. The therapy was thereby adjusted according to the patients’ needs. During that period, the subjects of the control group met the researcher at the beginning of the study and after 4 weeks for blood pressure measuring. Antihypertensives were given, in both groups, according to the algorithm from the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (ESH/ESC) [27]. In both groups, antihypertensives were selected from five classes of antihypertensive agents—thiazide diuretics, calcium antagonists, ACE-inhibitors, angiotensin receptor blockers, and beta blockers—taking into account the characteristics of the patient. Antihypertensive agents are used as monotherapy or in combinations of two or more drugs. No one group of antihypertensives was given priority in the choice of therapy, both in the experimental group and the control group. Antidepressant therapy was prescribed from the group of selective serotonin re-uptake inhibitors (SSRIs), based on recommendations for treating depression in primary healthcare [32, 33]. The selection of
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antidepressants and their dosage was made in relation to the presence of physical illness and possible interactions, as well as anticipated side-effects and prevailing symptoms. A psychiatrist from a medical advisory body was consulted, as required. Five types of antidepressants were used in treating depression in hypertensive patients. Sertraline was most widely used; it was administered to 37 patients (50.69%). Twenty-five (34.25%) of the patients were administered paroxetine, seven patients (9.59%) were administered fluvoxamine, two (2.74%) received fluoxetine, and two (2.74%) received tianeptine. The doses of the antidepressants were at the level of treatment. Based on the patients’ medical records, the history of their visits and drug prescription records, the regular intake of antihypertensive and antidepressant therapy was controlled. After the 24-week period ended, patients from the experimental and control groups were again subjected to the BDI. A difference in mean values of blood pressure and a difference in depression levels before and after antidepressant therapy was obtained. The continuation of the therapy was determined based on indications, in agreement with the patients and in cooperation with a consultant psychiatrist. Analysis Data were analyzed with appropriate statistical tests. In order to process the research results, all the variables were tested using the Kolmogorov-Smirnov test for normality of distribution. The median value was used as a measure of a central tendency. The Wilcoxon test for paired samples was employed for testing dependent variables and the Mann-Whitney test was used for independent variables. The Chi-square test was used to examine gender and age differences. The significance level was set at P < 0.05. In order to assess the impact of antidepressant therapy (independent variable) on systolic and diastolic blood pressure (dependent variables), the Wilcoxon test for paired samples was employed. The Pearson coefficient of correlation was calculated between a decrease of blood pressure level and a decrease of depression level. Statistical analysis was carried out using Statistica 9 (Statsoft Inc., Tulsa, SAD). RESULTS Hypertensive Patients—Full Sample Patients with arterial hypertension in this research (N = 452) had a median age of 67 years, (C = 67 (range 48-82)). The research included 264 women (58.4%) and 188 men (41.6%). The Chi-square test was used to ensure that there was no statistically significant difference in the number of men and women among hypertensive patients (c2 = 3.31, P = 0.069). The median of systolic blood pressure was 142 mmHg (C = 142 (range 124-163)), while the median of diastolic blood pressure was 83 mmHg (C = 83 (range 75-95)).
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The majority of subjects, 53% (N = 238), was administered only one antihypertensive; 37% (N = 169) of participants used two antihypertensives, while 9% of participants (N = 40) used three antihypertensives. Only 1% (N = 5) of participants were administered four antihypertensives, which represented the largest number of simultaneously-used hypertensives. According to the Beck Depression Inventory, it was found that 51.5% (N = 233) hypertensive patients were non-depressed, 19.7% (N = 89) were mildly depressed, 26.3% (N = 119) were moderately depressed, and 2.4% (N = 11) were severely depressed. There were 29.6% (N = 134) depressed hypertensive patients, who were found to be mildly depressed (BDI > 16), namely moderately and severely depressed, and 70.4% (N = 318) non-depressed hypertensive patients who were non-depressed or mildly depressed (BDI = 16). The Mann-Whitney U test was used to determine that depressed hypertensive patients had statistically higher values of systolic and diastolic blood pressure compared to non-depressed subjects. The mean blood pressure values in the group of depressed hypertensive patients and non-depressed hypertensive patients are presented in Table 1. Depressed Hypertensive Patients Among the group of depressed hypertensive patients (N = 134), there were 67.9% (N = 91) women and 32.1% (N = 43) men, and among the non-depressed hypertensive patients there were 54.4% (N = 173) women and 45.6% (N = 145) men. The Chi-square test showed that there were statistically more women than men among the group of depressed hypertensive patients (c2 = 7.081; p = 0.008). Of the 134 depressed hypertensive patients, 54.5% (N = 73) were treated both with antidepressants and antihypertensives (the experimental group), while 45.5% (N = 61) of patients were treated only with antihypertensives (the control
Table 1. Blood Pressure Levels in Depressed and Non-Depressed Hypertensive Patients C Systolic blood pressure (N = 452) Depressed N = 134 150 Non-depressed N = 318 138 Diastolic blood pressure (N = 452) Depressed N = 134 Non-depressed N = 318
88 81
Min Max
123 113
72 53
5th 95th
Statistics
192 133 167 Mann-Whitney U test 175 122 158 Z = 9.77, P < 0.001
108 105
78 75
98 Mann-Whitney U test 92 Z = 10.57, P < 0.001
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group). It was determined that there was no statistically significant difference between the experimental and the control group, either in gender (using the Chi-square test), age, depression level, or number of antihypertensives (using the Mann-Whitney U test). It was also determined that the experimental group of patients had significantly higher values of both systolic and diastolic blood pressure compared to the control group of patients (Table 2).
Table 2. Comparison of the Experimental and Control Groups Regarding Age, Gender, Blood Pressure, Number of Antihypertensives and Depression Levels Total N = 134
Experimental group N = 73 N (%)
Control group N = 61 N (%)
Gender M F
19 (26.0) 54 (74.0)
24 (39.3) 37 (60.7)
69 28-85
68 47-86
Mann-Whitney U test Z = 0.37 P = 0.708
Systolic blood pressure Median Range
155 137-192
143 123-162
Mann-Whitney U test Z = 6.99 P < 0.001
Diastolic blood pressure Median Range
90 78-108.3
85 71.67-95
Mann-Whitney U test Z = 5.24 P = 0.001
The number of antihypertensives Median Range
2 1-4
2 1-4
Mann-Whitney U test Z = 0.66 P = 0.056
Depression level Median Range
21 17-37
20 17-39
Mann-Whitney U test Z = 0.58 P = 0.564
Age Median Range
Statistics c2 = 3.31 P = 0.069
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Experimental Group in the 1st and the 2nd Stage of Blood Pressure Measuring: The Results of Treating Depressive Hypertensive Patients with Antidepressants The systolic and diastolic blood pressure of 89.0% of subjects (N = 65) significantly decreased after the 24-week antidepressant therapy (2nd measuring). The median of systolic blood pressure in the first stage of measuring was 155 mmHg (C = 155 (5th to 95th percentile 137-192)), and 128 mmHg (C = 128 (5th to 95th percentile 112-161)) in the second stage of measuring. The median of diastolic blood pressure in the first stage of measuring was 90 mmHg (C= 90 (5th to 95th percentile 78-108)), and 73 mmHg (C = 73 (5th to 95th percentile 58-93)) in the second stage of measuring (Table 3). The blood pressure of 11.0% subjects (N = 8) remained the same after the 24-week antidepressant therapy. After completion of the 24-week antidepressant therapy, administration of one of the antihypertensives was terminated for 9.6% (N = 7) of the patients of the experimental group due to a significant drop in blood pressure and satisfactory regulation. It was found that the experimental groups’ patients’ depressions levels were significantly lower after taking antidepressants (Beck 2) compared to their depression levels before treatment (Beck 1), (Beck 1 C = 21 (5th to 95th percentile 17-37)); (Beck 2 C = 8 (5th to 95th percentile 4-20)) (Table 3). The decrease of systolic blood pressure is positively correlated with a decrease of depression levels on the Beck Depression Inventory (r = 0.27, P = 0.020; (CI 95% 0.4476-0.4720)) and the decrease of diastolic blood pressure is positively correlated with the decrease of depression levels on the Beck Depression Inventory (r = 0.38, P < 0.0010, (CI 95% 0.1665-0.5625)). The Control Group in the 1st and the 2nd Stage of Blood Pressure Measuring The Wilcoxon test of paired samples showed that among the control group of patients, there was no statistically significant difference in blood pressure levels and depression levels between the 1st (at the beginning of the study) and the 2nd measuring (after 24 weeks) (Table 3). Comparison of Blood Pressure Levels in the Experimental and Control Group After 24 Weeks After the completion of antidepressant therapy, the systolic and diastolic blood pressure levels in the experimental group of patients (with antidepressants) were lower compared to the systolic and diastolic blood pressure levels of the control group. In the experimental group, the median of systolic blood pressure in the second measuring, after taking antidepressants, was 128 mm Hg (C = 128 (5th to 95th percentile 112-161)), and the median of diastolic blood pressure was 73 mmHg (C = 73 (5th to 95th percentile 58-93)). In the control group (without
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Table 3. Systolic and Diastolic Blood Pressure and Depression Levels in the Experimental and Control Groups of Patients for the 1st and 2nd Measurings C
Min
Max
5th
95th
Statistics
155 128
137 112
192 161
142 117
172 155
Wilcoxon test Z = 7.42, P < 0.001
Diastolic 1c Diastolic 2d
90 73
78 58
108 93
83 68
98 88
Wilcoxon test Z = 7.36, P < 0.001
Beck 1e Beck 2f
21 8
17 4
37 20
17 4
32 17
Wilcoxon test Z = 7.42, P < 0.001
Control group N = 61 Systolic 1a Systolic 2b
143 142
123 122
162 158
128 126
157 155
Wilcoxon test Z = 0.70, P < 0.484
Diastolic 1c Diastolic 2d
85 85
72 77
95 96
77 78
92 93
Wilcoxon test Z = 0.43, P < 0.666
Beck 1e Beck 2f
20 20
17 16
39 37
17 4
32 17
Wilcoxon test Z = 0.21, P < 0.836
Experimental group N = 73 Systolic 1a Systolic 2b
aSystolic 1 = Systolic pressure taken during the first measuring (at the beginning of the study). bSystolic 2 = Systolic pressure taken during the second measuring (after 24 weeks). cDiastolic 1 = Diastolic pressure taken during the first measuring (at the beginning of the study). dDiastolic 2 = Diastolic pressure taken during the second measuring (after 24 weeks). eBeck 1 = First measuring (at the beginning of the study). fBeck 2 = Second measuring (after 24 weeks).
antidepressants), the median of systolic blood pressure in the second measuring was 142 mm Hg (C = 142 (5th to 95th percentile 122-158)) and the median of diastolic blood pressure was 85 mm Hg (C = 85 (5th to 95th percentile 77,96)). The difference is statistically significant for systolic (Z = 7.22; P < 0.001) and diastolic blood pressure (Z = 8.48; P < 0.001). DISCUSSION Hypertensive Patients with Undetected Depression Hypertensive patients included in this study were elderly. There was no statistically significant difference in the proportion of men and women, which is
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consistent with data from the literature [1]. Our results showed that 29.6% of patients with arterial hypertension were depressed, which was undetected prior to the research. Most of them (27.2%) were mildly or moderately depressed, and 2.4% were severely depressed. It is known that severe depression is more easily detected by primary care physicians. However, moderate depression is undetected in more than 50% of cases [3, 33]. The number of hypertensive patients with undetected depression in our research probably corroborates such results. Depression and hypertension are common diseases in the general population and often occur concurrently (10, 34-38]. According to the available data, the prevalence of arterial hypertension in primary care is 39%-43% [34, 35]. Regarding depressive disorders, the current prevalence rate in primary care is 7.3%-18.5% [36, 37]. Even though many studies focus on the correlation between depression and hypertension, a relatively small number of studies deal with the frequency of depression linked to hypertension [15]. In our research, there were statistically more women with depression and hypertension than men, which is in accordance with currently known data about the higher prevalence of women among the depressive patients [3, 36]. Systolic and Diastolic Blood Pressure in Depressed Patients with Hypertension The median of systolic and diastolic blood pressure in depressed hypertensive patients in our research were significantly higher (150/88 mmHg) compared to non-depressed hypertensive patients (138/81 mmHg). These results are compatible with the data in the literature, which state that the co-morbidity of depression and hypertension and/or other somatic illnesses aggravates the course of illness and makes treatment more difficult [39, 40]. This explanation can be linked with data from most of the studies that focus on depression, finding that depression can adversely affect self-care [3]. The relation between hypertension and depression is complex. The reasons for the concurrence of these two illnesses may lie in the joint pathophysiological mechanisms of hypertension and depression, primarily in the hyperactivity of the sympathetic nervous system and genetic influence [16]. Other pathophysiological mechanisms can serve as an explanation for these results: sleep disorder, reduced central serotonin transporters, increased cortisol levels, chronic stress, and elevated C-reactive protein levels [17, 41-45]. Depression may worsen the course of hypertension because it is also associated with an increased risk of obesity, a sedentary lifestyle, smoking, and poor adherence to medication [10]. However, the relation is bidirectional. Hypertension and target organ damage, and some antihypertensive drugs, can influence the occurrence of depression.
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The Results of Treating Depressive Hypertensive Patients with Antidepressants After 24 weeks of taking antidepressants, systolic and diastolic pressures in hypertensive patients with depression were significantly lower. Such results could confirm the positive impact of treating depression on blood pressure regulation. It is possible that a drop in the depression level accompanied by an improvement of the clinical picture triggered by the above-mentioned pathophysiological mechanisms subsequently leads to a decrease in arterial blood pressure. Moreover, treating the basic symptoms of depression leads to improvements in a person’s everyday life. Such persons are more likely to be physically active, have a healthier diet, and tend to cooperate in treatment [9]. In 10% of patients who were receiving combined hypertension therapy, the administration of one of the antihypertensives was terminated due to a significant decrease in blood pressure and an appropriate blood pressure regulation. This result confirms the positive impact of treating depression in hypertensive patients, and points to economic aspects in identifying and treating depression in hypertensive patients. Blood pressure in 89% of the patients was significantly reduced, while in 11% of the patients no change in blood pressure was recorded. Although antidepressants from the group of selective serotonin re-uptake inhibitors undeniably represent a breakthrough in treating depression, certain deficiencies in the therapy remain unresolved [46, 47]. The results indicate that treating hypertensive patients with antidepressants leads to a greater than 20/10 mmHg decrease in their blood pressures. This finding could represent a significant drop in cardiovascular risk, given the fact that all the observed patients were aged 40-70 [48]. This is consistent with other studies showing that the link between depression and cardiovascular death is indirect and is relevant to the treatment of hypertension [41]. The detection of hypertensive patients suffering from depression would improve medication adherence, depressive symptoms, and blood pressure control in those patients with both chronic illnesses [49]. In our study, medication adherence was monitored only by the dynamics of raising recipes, based on medical records. However, the actual consumption of drugs has not been tested, and there were no potential differences at the beginning or the end of the study. Limitation of the Study The limitations of this research involve its relatively small sample size and an incomplete homogeneity in the experimental and control groups. We also did not take into account the personality traits, way of life, or habits of hypertensive patients with depression. Additional research in this area is necessary.
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46. Kellner M, Demiralay C, Muhtz C, Husemann J, Kölsch W, Hiemke C, Yassouridis A, Wiedemann K. No effect of six weeks of treatment with escitalopram on mood in healthy volunteers—Irrespective of genotype for the promoter of the serotonin transporter. Psychiatry Research 2008;161:339-343. 47. Gilles M, Deuschle M, Kellner S, Shams M, Krumm B, Härtter S, Heuser I, Hiemke C. Paroxetine serum concentrations in depressed patients and response to treatment. Pharmacopsychiatry 2005;38:118-121. 48. MacMahon S. Blood pressure and the risk of cardiovascular disease. New England Journal of Medicine 2000;342:50-51. 49. Krousel-Wood M, Frohlich ED. Hypertension and depression: Coexisting barriers to medication adherence. Journal of Hypertension 2010;12:481-486.
Direct reprint requests to: Ines Dimini-Lisica Department of Family Medicine School of Medicine University of Rijeka B. Branchetta 20 Rijeka 51000, Croatia e-mail: [email protected]
OUTCOME OF TREATMENT WITH ANTIDEPRESSANTS IN PATIENTS WITH HYPERTENSION AND UNDETECTED DEPRESSION
INES DIMINIC-LISICA BRANISLAVA POPOVIC University of Rijeka, Croatia JELENA REBIC KBC Rijeka, Croatia MIRO KLARIC Mostar Clinical Hospital, Bosnia and Herzegovina TANJA FRANCIŠKOVIC University of Rijeka, Croatia
ABSTRACT
Objective: The objective of the research was to determine whether the administration of antidepressants, concurrently with antihypertensive therapy, leads to the better regulation of blood pressure in patients with hypertension and increased depressiveness. Methods: Research was conducted in two outpatient family clinics in Rijeka, Croatia, on 452 patients with arterial hypertension who had not been diagnosed with depression prior to the study. The diagnosis of hypertension was made in accordance with the European Society of Hypertension and the European Society of Cardiology Guidelines for the Management of Arterial Hypertension. Using the Beck Depression Inventory and the ICD-10 criteria for depression, a group of depressed hypertensive patients (N = 134) was selected. Out of a total of 134 selected patients, 73 patients (N = 73) were receiving antidepressants together with antihypertensives for 24 weeks. They formed the experimental group. The rest of the patients (N = 61) continued to receive only antihypertensives and 115 Ó 2014, Baywood Publishing Co., Inc. doi: http://dx.doi.org/10.2190/PM.47.2.c http://baywood.com
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they formed the control group. Results: After the end of the 24-week therapy, the experimental group of patients had significantly lower levels of both systolic and diastolic blood pressure (Z = 7.42; P < 0.001; and Z = 7.36; P < 0.001). The control group saw no significant difference between the level of blood pressure (both systolic and diastolic) prior to and after this period. Conclusion: The application of antidepressant therapy in patients with hypertension who are also depressed may be associated with the better control of blood pressure, which reduces the risk of cardiovascular disease in addition to alleviating depressive symptoms. (Int’l. J. Psychiatry in Medicine 2014;47:115-129)
Key Words: antidepressants, hypertension, undetected depression, blood pressure regulation
INTRODUCTION Depression and hypertension are highly prevalent diseases in the modern world [1-3]. A substantial literature supports clinically important associations between psychiatric illness and chronic medical conditions [4]. An increase in the prevalence of hypertension, as well as insufficient regulation of blood pressure and a concomitant of premature mortality from cardiovascular disease, require more extensive research into risk factors and aspects of the prevalence of these illnesses [5-8]. Depressive disorders are prevalent among the medically ill and it is known that depressive disorder can negatively affect the course of physical illness [9, 10]. Numerous studies suggest an association between increased cardiovascular mortality, heart failure, and high blood pressure with depression [11-16]. The presence of co-morbid illnesses, such as depression, can be one of the causes of the inadequate regulation of blood pressure. The link between two very common illnesses among the population—hypertension and depression—has not yet been adequately examined. A considerable number of recent studies deal with the joint neurophysiological mechanisms as well as the joint genetic risk factors of hypertension and depression [17-22]. Depressive symptoms may be an important modifiable barrier to antihypertensive medication adherence in older adults [23]. Co-morbid depression in somatic patients often passes unnoticed and remains untreated [3, 24]. This fact is not sufficiently taken into account in daily practice. However, we should consider that treating depression with antidepressants leads to a reduction of depression symptoms and decreases blood pressure levels [25]. Cooperation between primary care and psychiatric services significantly helps with results [26]. The purpose of this study was to determine whether, among patients with essential hypertension, there are those who suffer from unrecognized depressive symptoms, and whether using antidepressants concurrently with antihypertensive drugs leads to the better control of blood pressure.
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METHODS The research was conducted from February to December 2009 in two outpatient family medicine clinics caring for 2,550 persons in Rijeka, Croatia. Participants The study included patients with chronic arterial hypertension. Of 595 registered patients with arterial hypertension, 72 (12.10%) were unavailable due to the temporary absence from their place of residence or as a result of the irregular attendance of routine checkups and 16 (2.68%) patients refused to participate in the study. The study excluded 10 (1.68%) patients with severe physical illnesses and general disability, as well as 14 (2.35%) patients with secondary hypertension and 31 (5.21%) patients with a history of mental disorders. Thus, the study included 452 patients (or 75.96%) of registered hypertensive patients. All the patients involved in the study were adults, aged 23-90 years. The patients were informed of the research and they gave their written informed consent. Data from medical records and data obtained by questionnaires were presented anonymously and the patients’ identities were protected. The study was approved by the Ethics Committee School of Medicine, University of Rijeka. Procedures Arterial hypertension diagnosis was established according to ESH/ESC guidelines [27] or based on the criteria of being treated with antihypertensives. The patients were included in accordance with their order of arrival at the clinic for a routine check-up or the continuation of therapy. In order to determine general demographic data, the subjects responded to a specially-designed, general questionnaire. The general questionnaire contained demographic questions referring to participants in general as well as questions referring to co-morbid chronic illnesses and medication therapies. Information on chronic illness and medication therapies was checked in the subjects’ medical records. In order to identify depression levels, the Beck Depression Inventory [28, 29] was used. The Beck Depression Inventory (BDI) is a self-evaluation instrument consisting of 21 items. The scores range from 0 to 63. The standard cutoffs are as follows: 0–9 indicates non-depressed, 10-18 indicates mildly-moderately depressed, 19-29 indicates moderately-severely depressed, and 30–63 indicates severely depressed [28, 29]. In this study, we defined a cutoff >16 because of the higher sensitivity and specificity of the test and greater clinical relevance ([30, 31]. Based on the BDI, the subjects were divided into two groups: the non-depressed group, which also included mildly depressed subjects (BDI £ 16), and a group of depressed patients, which included mildly depressed subjects with (BDI > 16) moderately and severely depressed.
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Among a group of depressed patients, researchers (family physicians) confirmed depression by the ICD-10 criteria for depression, and it was supervised by a psychiatrist. All the patients met the criteria for a depressive episode-type major depression that lasted longer than 2 weeks. The researchers compared the blood pressure levels between the groups. During the research, all the patients with BDI scores higher than 16 were monitored over a period of 24 weeks. This group consisted of 134 patients. These patients had a depressive disorder that was not detected prior to the research. These patients were recommended antidepressants together with antihypertensives. Out of a total of 134 patients with arterial hypertension and depression, only 73 began and continued receiving antidepressants with antihypertensives for 24 weeks. They formed the experimental group. Out of a total of 134 hypertensive patients with depression, 61 did not receive antidepressants for a variety of reasons. These patients did not receive any other treatment, such as psychotherapy, unless with the support of family physicians at every visit. They formed the control group. Of 61 such patients, 29 patients rejected antidepressants, offering many explanations (“I’m taking too many drugs,” “I’ll think about it,” etc.), 19 patients started taking antidepressants, but failed to cooperate and terminated their therapy, and seven patients ended their treatment due to drug intolerance or side-effects. This group also included six patients who stopped using antidepressants because of the independent occurrence of various health problems and the use of hospital health services. At the beginning and the end of the research, the subjects’ blood pressures were measured three times a fortnight. The mean values of their blood pressures were calculated afterwards. Blood pressure was taken by using a mercury sphygmomanometer with appropriate cuffs, after the patients had been sitting relaxed for at least 5 minutes. Blood pressure was taken once every 4 weeks throughout the research among both groups. In the first month of taking antidepressants, the experimental group had regular checkups after the 7th, 14th, and 28th day of their antidepressant therapy. The therapy was thereby adjusted according to the patients’ needs. During that period, the subjects of the control group met the researcher at the beginning of the study and after 4 weeks for blood pressure measuring. Antihypertensives were given, in both groups, according to the algorithm from the European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (ESH/ESC) [27]. In both groups, antihypertensives were selected from five classes of antihypertensive agents—thiazide diuretics, calcium antagonists, ACE-inhibitors, angiotensin receptor blockers, and beta blockers—taking into account the characteristics of the patient. Antihypertensive agents are used as monotherapy or in combinations of two or more drugs. No one group of antihypertensives was given priority in the choice of therapy, both in the experimental group and the control group. Antidepressant therapy was prescribed from the group of selective serotonin re-uptake inhibitors (SSRIs), based on recommendations for treating depression in primary healthcare [32, 33]. The selection of
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antidepressants and their dosage was made in relation to the presence of physical illness and possible interactions, as well as anticipated side-effects and prevailing symptoms. A psychiatrist from a medical advisory body was consulted, as required. Five types of antidepressants were used in treating depression in hypertensive patients. Sertraline was most widely used; it was administered to 37 patients (50.69%). Twenty-five (34.25%) of the patients were administered paroxetine, seven patients (9.59%) were administered fluvoxamine, two (2.74%) received fluoxetine, and two (2.74%) received tianeptine. The doses of the antidepressants were at the level of treatment. Based on the patients’ medical records, the history of their visits and drug prescription records, the regular intake of antihypertensive and antidepressant therapy was controlled. After the 24-week period ended, patients from the experimental and control groups were again subjected to the BDI. A difference in mean values of blood pressure and a difference in depression levels before and after antidepressant therapy was obtained. The continuation of the therapy was determined based on indications, in agreement with the patients and in cooperation with a consultant psychiatrist. Analysis Data were analyzed with appropriate statistical tests. In order to process the research results, all the variables were tested using the Kolmogorov-Smirnov test for normality of distribution. The median value was used as a measure of a central tendency. The Wilcoxon test for paired samples was employed for testing dependent variables and the Mann-Whitney test was used for independent variables. The Chi-square test was used to examine gender and age differences. The significance level was set at P < 0.05. In order to assess the impact of antidepressant therapy (independent variable) on systolic and diastolic blood pressure (dependent variables), the Wilcoxon test for paired samples was employed. The Pearson coefficient of correlation was calculated between a decrease of blood pressure level and a decrease of depression level. Statistical analysis was carried out using Statistica 9 (Statsoft Inc., Tulsa, SAD). RESULTS Hypertensive Patients—Full Sample Patients with arterial hypertension in this research (N = 452) had a median age of 67 years, (C = 67 (range 48-82)). The research included 264 women (58.4%) and 188 men (41.6%). The Chi-square test was used to ensure that there was no statistically significant difference in the number of men and women among hypertensive patients (c2 = 3.31, P = 0.069). The median of systolic blood pressure was 142 mmHg (C = 142 (range 124-163)), while the median of diastolic blood pressure was 83 mmHg (C = 83 (range 75-95)).
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The majority of subjects, 53% (N = 238), was administered only one antihypertensive; 37% (N = 169) of participants used two antihypertensives, while 9% of participants (N = 40) used three antihypertensives. Only 1% (N = 5) of participants were administered four antihypertensives, which represented the largest number of simultaneously-used hypertensives. According to the Beck Depression Inventory, it was found that 51.5% (N = 233) hypertensive patients were non-depressed, 19.7% (N = 89) were mildly depressed, 26.3% (N = 119) were moderately depressed, and 2.4% (N = 11) were severely depressed. There were 29.6% (N = 134) depressed hypertensive patients, who were found to be mildly depressed (BDI > 16), namely moderately and severely depressed, and 70.4% (N = 318) non-depressed hypertensive patients who were non-depressed or mildly depressed (BDI = 16). The Mann-Whitney U test was used to determine that depressed hypertensive patients had statistically higher values of systolic and diastolic blood pressure compared to non-depressed subjects. The mean blood pressure values in the group of depressed hypertensive patients and non-depressed hypertensive patients are presented in Table 1. Depressed Hypertensive Patients Among the group of depressed hypertensive patients (N = 134), there were 67.9% (N = 91) women and 32.1% (N = 43) men, and among the non-depressed hypertensive patients there were 54.4% (N = 173) women and 45.6% (N = 145) men. The Chi-square test showed that there were statistically more women than men among the group of depressed hypertensive patients (c2 = 7.081; p = 0.008). Of the 134 depressed hypertensive patients, 54.5% (N = 73) were treated both with antidepressants and antihypertensives (the experimental group), while 45.5% (N = 61) of patients were treated only with antihypertensives (the control
Table 1. Blood Pressure Levels in Depressed and Non-Depressed Hypertensive Patients C Systolic blood pressure (N = 452) Depressed N = 134 150 Non-depressed N = 318 138 Diastolic blood pressure (N = 452) Depressed N = 134 Non-depressed N = 318
88 81
Min Max
123 113
72 53
5th 95th
Statistics
192 133 167 Mann-Whitney U test 175 122 158 Z = 9.77, P < 0.001
108 105
78 75
98 Mann-Whitney U test 92 Z = 10.57, P < 0.001
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group). It was determined that there was no statistically significant difference between the experimental and the control group, either in gender (using the Chi-square test), age, depression level, or number of antihypertensives (using the Mann-Whitney U test). It was also determined that the experimental group of patients had significantly higher values of both systolic and diastolic blood pressure compared to the control group of patients (Table 2).
Table 2. Comparison of the Experimental and Control Groups Regarding Age, Gender, Blood Pressure, Number of Antihypertensives and Depression Levels Total N = 134
Experimental group N = 73 N (%)
Control group N = 61 N (%)
Gender M F
19 (26.0) 54 (74.0)
24 (39.3) 37 (60.7)
69 28-85
68 47-86
Mann-Whitney U test Z = 0.37 P = 0.708
Systolic blood pressure Median Range
155 137-192
143 123-162
Mann-Whitney U test Z = 6.99 P < 0.001
Diastolic blood pressure Median Range
90 78-108.3
85 71.67-95
Mann-Whitney U test Z = 5.24 P = 0.001
The number of antihypertensives Median Range
2 1-4
2 1-4
Mann-Whitney U test Z = 0.66 P = 0.056
Depression level Median Range
21 17-37
20 17-39
Mann-Whitney U test Z = 0.58 P = 0.564
Age Median Range
Statistics c2 = 3.31 P = 0.069
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Experimental Group in the 1st and the 2nd Stage of Blood Pressure Measuring: The Results of Treating Depressive Hypertensive Patients with Antidepressants The systolic and diastolic blood pressure of 89.0% of subjects (N = 65) significantly decreased after the 24-week antidepressant therapy (2nd measuring). The median of systolic blood pressure in the first stage of measuring was 155 mmHg (C = 155 (5th to 95th percentile 137-192)), and 128 mmHg (C = 128 (5th to 95th percentile 112-161)) in the second stage of measuring. The median of diastolic blood pressure in the first stage of measuring was 90 mmHg (C= 90 (5th to 95th percentile 78-108)), and 73 mmHg (C = 73 (5th to 95th percentile 58-93)) in the second stage of measuring (Table 3). The blood pressure of 11.0% subjects (N = 8) remained the same after the 24-week antidepressant therapy. After completion of the 24-week antidepressant therapy, administration of one of the antihypertensives was terminated for 9.6% (N = 7) of the patients of the experimental group due to a significant drop in blood pressure and satisfactory regulation. It was found that the experimental groups’ patients’ depressions levels were significantly lower after taking antidepressants (Beck 2) compared to their depression levels before treatment (Beck 1), (Beck 1 C = 21 (5th to 95th percentile 17-37)); (Beck 2 C = 8 (5th to 95th percentile 4-20)) (Table 3). The decrease of systolic blood pressure is positively correlated with a decrease of depression levels on the Beck Depression Inventory (r = 0.27, P = 0.020; (CI 95% 0.4476-0.4720)) and the decrease of diastolic blood pressure is positively correlated with the decrease of depression levels on the Beck Depression Inventory (r = 0.38, P < 0.0010, (CI 95% 0.1665-0.5625)). The Control Group in the 1st and the 2nd Stage of Blood Pressure Measuring The Wilcoxon test of paired samples showed that among the control group of patients, there was no statistically significant difference in blood pressure levels and depression levels between the 1st (at the beginning of the study) and the 2nd measuring (after 24 weeks) (Table 3). Comparison of Blood Pressure Levels in the Experimental and Control Group After 24 Weeks After the completion of antidepressant therapy, the systolic and diastolic blood pressure levels in the experimental group of patients (with antidepressants) were lower compared to the systolic and diastolic blood pressure levels of the control group. In the experimental group, the median of systolic blood pressure in the second measuring, after taking antidepressants, was 128 mm Hg (C = 128 (5th to 95th percentile 112-161)), and the median of diastolic blood pressure was 73 mmHg (C = 73 (5th to 95th percentile 58-93)). In the control group (without
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Table 3. Systolic and Diastolic Blood Pressure and Depression Levels in the Experimental and Control Groups of Patients for the 1st and 2nd Measurings C
Min
Max
5th
95th
Statistics
155 128
137 112
192 161
142 117
172 155
Wilcoxon test Z = 7.42, P < 0.001
Diastolic 1c Diastolic 2d
90 73
78 58
108 93
83 68
98 88
Wilcoxon test Z = 7.36, P < 0.001
Beck 1e Beck 2f
21 8
17 4
37 20
17 4
32 17
Wilcoxon test Z = 7.42, P < 0.001
Control group N = 61 Systolic 1a Systolic 2b
143 142
123 122
162 158
128 126
157 155
Wilcoxon test Z = 0.70, P < 0.484
Diastolic 1c Diastolic 2d
85 85
72 77
95 96
77 78
92 93
Wilcoxon test Z = 0.43, P < 0.666
Beck 1e Beck 2f
20 20
17 16
39 37
17 4
32 17
Wilcoxon test Z = 0.21, P < 0.836
Experimental group N = 73 Systolic 1a Systolic 2b
aSystolic 1 = Systolic pressure taken during the first measuring (at the beginning of the study). bSystolic 2 = Systolic pressure taken during the second measuring (after 24 weeks). cDiastolic 1 = Diastolic pressure taken during the first measuring (at the beginning of the study). dDiastolic 2 = Diastolic pressure taken during the second measuring (after 24 weeks). eBeck 1 = First measuring (at the beginning of the study). fBeck 2 = Second measuring (after 24 weeks).
antidepressants), the median of systolic blood pressure in the second measuring was 142 mm Hg (C = 142 (5th to 95th percentile 122-158)) and the median of diastolic blood pressure was 85 mm Hg (C = 85 (5th to 95th percentile 77,96)). The difference is statistically significant for systolic (Z = 7.22; P < 0.001) and diastolic blood pressure (Z = 8.48; P < 0.001). DISCUSSION Hypertensive Patients with Undetected Depression Hypertensive patients included in this study were elderly. There was no statistically significant difference in the proportion of men and women, which is
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consistent with data from the literature [1]. Our results showed that 29.6% of patients with arterial hypertension were depressed, which was undetected prior to the research. Most of them (27.2%) were mildly or moderately depressed, and 2.4% were severely depressed. It is known that severe depression is more easily detected by primary care physicians. However, moderate depression is undetected in more than 50% of cases [3, 33]. The number of hypertensive patients with undetected depression in our research probably corroborates such results. Depression and hypertension are common diseases in the general population and often occur concurrently (10, 34-38]. According to the available data, the prevalence of arterial hypertension in primary care is 39%-43% [34, 35]. Regarding depressive disorders, the current prevalence rate in primary care is 7.3%-18.5% [36, 37]. Even though many studies focus on the correlation between depression and hypertension, a relatively small number of studies deal with the frequency of depression linked to hypertension [15]. In our research, there were statistically more women with depression and hypertension than men, which is in accordance with currently known data about the higher prevalence of women among the depressive patients [3, 36]. Systolic and Diastolic Blood Pressure in Depressed Patients with Hypertension The median of systolic and diastolic blood pressure in depressed hypertensive patients in our research were significantly higher (150/88 mmHg) compared to non-depressed hypertensive patients (138/81 mmHg). These results are compatible with the data in the literature, which state that the co-morbidity of depression and hypertension and/or other somatic illnesses aggravates the course of illness and makes treatment more difficult [39, 40]. This explanation can be linked with data from most of the studies that focus on depression, finding that depression can adversely affect self-care [3]. The relation between hypertension and depression is complex. The reasons for the concurrence of these two illnesses may lie in the joint pathophysiological mechanisms of hypertension and depression, primarily in the hyperactivity of the sympathetic nervous system and genetic influence [16]. Other pathophysiological mechanisms can serve as an explanation for these results: sleep disorder, reduced central serotonin transporters, increased cortisol levels, chronic stress, and elevated C-reactive protein levels [17, 41-45]. Depression may worsen the course of hypertension because it is also associated with an increased risk of obesity, a sedentary lifestyle, smoking, and poor adherence to medication [10]. However, the relation is bidirectional. Hypertension and target organ damage, and some antihypertensive drugs, can influence the occurrence of depression.
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The Results of Treating Depressive Hypertensive Patients with Antidepressants After 24 weeks of taking antidepressants, systolic and diastolic pressures in hypertensive patients with depression were significantly lower. Such results could confirm the positive impact of treating depression on blood pressure regulation. It is possible that a drop in the depression level accompanied by an improvement of the clinical picture triggered by the above-mentioned pathophysiological mechanisms subsequently leads to a decrease in arterial blood pressure. Moreover, treating the basic symptoms of depression leads to improvements in a person’s everyday life. Such persons are more likely to be physically active, have a healthier diet, and tend to cooperate in treatment [9]. In 10% of patients who were receiving combined hypertension therapy, the administration of one of the antihypertensives was terminated due to a significant decrease in blood pressure and an appropriate blood pressure regulation. This result confirms the positive impact of treating depression in hypertensive patients, and points to economic aspects in identifying and treating depression in hypertensive patients. Blood pressure in 89% of the patients was significantly reduced, while in 11% of the patients no change in blood pressure was recorded. Although antidepressants from the group of selective serotonin re-uptake inhibitors undeniably represent a breakthrough in treating depression, certain deficiencies in the therapy remain unresolved [46, 47]. The results indicate that treating hypertensive patients with antidepressants leads to a greater than 20/10 mmHg decrease in their blood pressures. This finding could represent a significant drop in cardiovascular risk, given the fact that all the observed patients were aged 40-70 [48]. This is consistent with other studies showing that the link between depression and cardiovascular death is indirect and is relevant to the treatment of hypertension [41]. The detection of hypertensive patients suffering from depression would improve medication adherence, depressive symptoms, and blood pressure control in those patients with both chronic illnesses [49]. In our study, medication adherence was monitored only by the dynamics of raising recipes, based on medical records. However, the actual consumption of drugs has not been tested, and there were no potential differences at the beginning or the end of the study. Limitation of the Study The limitations of this research involve its relatively small sample size and an incomplete homogeneity in the experimental and control groups. We also did not take into account the personality traits, way of life, or habits of hypertensive patients with depression. Additional research in this area is necessary.
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Direct reprint requests to: Ines Dimini-Lisica Department of Family Medicine School of Medicine University of Rijeka B. Branchetta 20 Rijeka 51000, Croatia e-mail: [email protected]
