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Abstract

Objective

This study examined whether antihypertensive medications and other patient characteristics are associated with severe depressive symptoms in patients with hypertension.

Methods

Patients with a diagnosis of hypertension were recruited from the internal medicine outpatient clinics of a hospital in Amman, Jordan, into this cross-sectional study. Depression severity was assessed using the Patient Health Questionnaire-9 (PHQ-9); anxiety by the General Anxiety Disorder-7; sleep quality by the Insomnia Severity Index; and psychological stress by the Perceived Stress Scale. Multivariable binary logistic regression was used to examine the association between the different classes of antihypertensive medication and depressive symptoms.

Results

Of the 431 participants, 282 (65.4%) were men; 240 (55.7%) reported having type 2 diabetes; 359 (83.3%) had dyslipidemia; 142 (32.9%) were on beta-blockers; 197 (45.2%) were on ACE inhibitors or angiotensin receptor blockers; 203 (47.1%) were on metformin; and 133 (30.9%) were taking sulfonylurea. Severe depressive symptoms, indicated by scoring above the cut-off of 14 on the PHQ-9, were present in 165 (38.3%) patients. Severe depression was associated with younger age (<55 years) (OR = 3.15, 95% CI = 1.83-5.41, P < 0.001), unemployment (OR = 2.15, 95% CI = 1.15-4.00, P = 0.01), diabetes (OR = 1.81, 95% CI = 1.09-3.02, P = 0.02), severe anxiety (OR = 6.40, 95% CI = 3.64-11.28, P < 0.001), and severe insomnia (OR = 4.73, 95% CI = 2.85-7.82, P < 0.001).

Conclusion

Severe depressive symptoms were not associated with antihypertensive medications or other drugs used by hypertensive patients. Younger age, diabetes, anxiety, and insomnia were the primary correlates of depression.

Keywords

depression hypertension chronic medications

Introduction

Hypertension is a widespread disease that is considered a major risk factor for cardiovascular diseases such as type 2 diabetes and dyslipidemia, and is a leading cause of death worldwide.^1,2 Around 10.4 million deaths worldwide are attributed to hypertension each year.³ In the Middle East, the estimated prevalence of hypertension is around 33%.⁴

The association between hypertension and mental health is bi-directional.⁵ Depression is associated with negative behaviours and habits, such as lack of physical exercise, smoking, and lack of medication adherence thus exacerbating hypertension and cardiovascular diseases.^6,7 On the other hand, inflammation associated with hypertension could exacerbate depression⁸ For example, one in every five patients with coronary artery disease or heart failure is depressed. Additionally. nearly one in every three is depressed post-stroke.⁹

Anxiety is a state of uncertainty and fear of the future.¹⁰ Anxiety could contribute to depression through negative behaviour patterns, such as cigarette smoking, lack of physical exercise, and excessive alcohol intake.

Biologically, chronic and uncontrolled anxiety activates the sympathetic system and the hypothalamus-pituitary axis, thus enhancing catecholamines and endothelial dysfunction.¹¹

Insomnia is a prevalent sleep disorder characterized by a lack of quality sleep and sleep latency.¹² The relationship between insomnia and depression is well-established. Insomnia increases the risk for depression through disrupted emotion; on the other hand, insomnia is a manifestation of depression symptoms.¹³

Antihypertensive drugs are the mainstay treatment for hypertension. Evidence about the effect of antihypertensive drugs on mental health is emerging.⁹ The use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been associated with improved mental health domains.^9,14 Additionally, several studies have reported that calcium channel blockers (CCBs) have been associated with decreased risk of developing depression, perhaps as a result of the calcium regulatory mechanism.^15,16 The effect of β-blockers and diuretics on mood disorders is, as yet, controversial.^17,18 Depression is one of the main side effects that is reported in patients on beta-blocker medications.^19,20 In patients with coronary artery disease, beta-blockers were associated with a higher risk of depression.²¹ Furthermore, in an elderly population with hypertension living in Australia and the United States, a cross-sectional study found a positive association between depressive symptoms and the use of beta-blockers, this relationship was stronger in lipophilic and non-selective beta-blockers.¹⁴

In addition to the antihypertensive agents, patients could receive other chronic medications for the associated comorbidities such as type II diabetes and dyslipidemia. It is estimated that 30% of diabetic patients experience clinically significant depressive symptoms.²² Preclinical and clinical data suggest a potential role of metformin in improving depressive symptoms: however, the data is, as yet, inconclusive.²³ Dyslipidemia patients are at higher risk of developing cardiovascular diseases (CVD), and patients with CVD are at higher risk for depression.²⁴

Therefore, the current study objective is to investigate whether chronic medications and other patient-related factors are associated with severe depressive symptoms in a cohort of patients with hypertension.

Methods

Study design and participants

This cross-sectional study was approved by the Institutional Review Board of Yarmouk University, IRB project number (2/2023). Participants for their study were recruited from the internal medicine outpatient clinics at Prince Hamza Hospital, Amman, Jordan. All participants signed an electronic consent form prior to participating in the study.

Inclusion criteria

Patients with hypertension visiting the outpatient clinic were approached, and eligible participants were selected using the following inclusion criteria: 1. Diagnosed with hypertension according to the JNC8 guidelines²⁵ for at least one year, 2. Adhering to their current antihypertensive regimen for the past year according to the Morisky scale.

Exclusion criteria

Patients with established psychological disturbances, such as schizophrenia and other disorders that impair the patient’s ability and competency to fill in the study questionnaire and scales.

Data collection

After the orientation step at the clinics, an electronic link on Google forms was sent to the participants on the same day to ensure privacy. All the participants signed an electronic consent form before participation and had the right to withdraw from the study at any moment. The research team assisted illiterate participants and those unfamiliar with the online questionnaire, by reading out the study questionnaire over the phone for the participants.

The study instrument

Covariates

A self-administered structured online questionnaire was employed to cover the participants’ demographical and clinical data, including sex, age, body mass index, educational level, employment status, family history of hypertension, presence of comorbidities, and adherence. To evaluate adherence to the antihypertensive therapy, the Arabic-validated version of the Morisky scale was used.^26,27 The scale is comprised of four items, which are behaviours associated with medication non-adherence, e.g., “do you forget to take your medication?” with simple scoring options as yes and no. The Arabic translation was demonstrated to be reliable with a Cronbach’s alpha score of 0.82.²⁷ A score of three or less out of four reflects moderate adherence.

Chronic medications

To record chronic medications used by the patients, the approved list of antihypertensive medications, diabetes medications, and dyslipidemia medications dispensed by Prince Hamza’s internal medicine pharmacy was included in a checklist on the online questionnaire. To ensure the accuracy of data collection, both the generic name, the brand name, and the picture of the medication pack were all presented and checked out by the patients. The antihypertensive classes used were β-blockers (bisoprolol, atenolol), diuretics (hydrochlorothiazide), CCBs (amlodipine), ACEIs (enalapril) and ARBs (valsartan). Diabetes medications included metformin, sulfonylurea, and insulin, and dyslipidemia comprised atorvastatin only.

Anxiety assessment

The General Anxiety Disorder-7 (GAD-7) is a short, self-administered scale. It measures anxiety for the last two weeks with a score range from 0 to 21 with a cut-off score of >14 for severe anxiety symptoms.²⁸ GAD-7 has a sensitivity of 89% and specificity of 82% for diagnosing generalized anxiety disorder²⁹ and was previously used in Arab-speaking patients.²⁸

Insomnia assessment

The insomnia severity index -Arabic version ISI-A was used to evaluate sleep quality. Developed by Morin et al.,³⁰ the ISI consists of seven questions with Likert-type answers and a score range between 0-28 with a cut-off score of >14 for severe insomnia symptoms. The ISI is validated to be used in the Arabic language.³¹

Perceived stress assessment

Participants were assessed for psychological stress for the past month according to the Arabic version of the Perceived Stress Scale (PSS). The PSS was developed by Cohen and Williamson.³² It includes 14 items that are designed to measure individual stress for the last 30 days with a cut-off value of 14, reflecting clinically significant stress. The Arabic version was previously used for Arab-speaking patients.³³

Outcome variable: Depression

To assess depression severity, the Patient Health Questionnaire-9 (PHQ-9) Arabic-validated version was used. The PHQ-9 is a short, self-administered scale based on the nine Diagnostic and Statistical Manual of Mental Disorders-IV criteria for diagnosing depressive symptoms.³⁴ The PHQ-9 has a sensitivity of 88% and specificity of 88% for severe depression and was previously used in Arab-speaking patients. It measures depression for the last two weeks, and it has a score range between 0 to 27 with a cut-off score of > 14 for severe depression.^35–37

Statistical analysis

Descriptive statistics were used, including frequencies and percentages to describe the sample characteristics. To investigate the association between the different patients’ factors and the dependent variable (depression severity), a Chi-square analysis was performed. Candidate variables below the cut-off value of P < .10 were included in the multivariate regression. To identify independent associations between the potential factors and dependent variable, a multivariate binary logistic analysis was performed, adjusted for age, employment status, diabetes, anxiety, and insomnia with depression severity as the dependent variable. Statistical significance was set at 2-sided P < .05 and estimates were set at 95% CI.

Results

Response rate

Out of the 516 eligible patients approached, 53 declined participation, 19 did meet inclusion criteria and 13 were excluded because of incomplete data. Therefore, a total of 431 participants were included for analysis, with a response rate of 83.5%.

Characteristics of the participants

Of the 431 participants, 282 (65.4%) were men; 261 (60.6%) were 55 years old and above; 331 (77%) had a family history of hypertension; 240 (55.7%) reported having type 2 diabetes; 359 (83.3%) reported as having dyslipidemia; 142 (32.9%) were on beta-blockers; 197 (45.2%) on ACEIs/ ARBs; 203 (47.1%) were on metformin; 133 (30.9%) were on sulfonylurea; 165 (38.3%) reported severe depression; 115 (26.7%) reported severe anxiety; 152 (35.3%) reported severe insomnia and 321 (74.5%) reported severe stress. Table 1

Table 1.

Sample demographic and clinical data.

Factor	Category	n(%)
Sex	female	149 (34.6)
Sex	male	282 (65.4)
Age	Below 55	170 (39.4)
Age	55 and above	261 (60.6)
BMI	Below 25	77 (17.9)
BMI	25 and above	354 (82.1)
Marital status	single	76 (17.6)
Marital status	married	355 (82.4)
Employment status	unemployed	326 (75.6)
Employment status	employed	105 (24.4)
Education	High school	336 (78)
Education	University	95 (22)
Family history of HTN	no	99 (23)
Family history of HTN	yes	331 (77)
Having Diabetes	no	191 (44.3)
Having Diabetes	yes	240 (55.7)
Having Dyslipidemia	no	72 (16.7)
Having Dyslipidemia	yes	359 (83.3)
Using Metformin	no	188 (43.6)
Using Metformin	yes	203 (47.1)
Using Sulfonylurea	no	298 (69.1)
Using Sulfonylurea	yes	133 (30.9)
Using Insulin	no	384 (89.1)
Using Insulin	yes	47 (10.9)
Using β-blockers	no	281 (65.2)
Using β-blockers	yes	142 (32.9)
Using ACEIs/ARBs	no	234 (54.3)
Using ACEIs/ARBs	yes	197 (45.2)
Using Diuretics	no	381 (88.4)
Using Diuretics	yes	50 (11.6)
Using CCBS	no	376 (87.2)
Using CCBS	yes	53 (12.3)
Severe depressive symptoms	no	266 (61.7)
Severe depressive symptoms	yes	165 (38.3)
Severe anxiety symptoms	no	316 (73.3)
Severe anxiety symptoms	yes	115 (26.7)
Severe insomnia symptoms	no	279 (64.7)
Severe insomnia symptoms	yes	152 (35.3)
Severe perceived stress symptoms	no	110 (25.5)
Severe perceived stress symptoms	yes	321 (74.5)

Factors associated with severe depressive symptoms

Table 2 shows the associations between the patients' features and depression severity. For example, severe depressive symptoms were significantly (P < 0.05) associated with age, education, employment status, family history; severe anxiety; severe insomnia, and severe stress.

Table 2.

Association between patients factors and depression severity using chi-square analysis.

Factor	Category	Non severe Depressive symptoms n (%)	Severe Depressive symptoms n (%)	Chi-square P-value
Sex	female	85 (32)	64 (38.3)	.18
Sex	male	181 (68)	101 (61.2)	.18
Age	Below 55	83 (31.2)	87 (52.7)	<.001*
Age	55 and above	183 (68.8)	78 (47.3)	<.001*
BMI	Below 25	50 (18.8)	27 (16.4)	.61
BMI	25 and above	216 (81.2)	138 (83.6)	.61
Marital status	single	48 (18)	28 (17)	.79
Marital status	married	218 (82)	137 (83)	.79
Employment status	unemployed	193 (72.6)	133 (80.6)	.06*
Employment status	employed	73(27.4)	32 (19.4)	.06*
Education	High school	198 (74.4)	138 (83.6)	.03*
Education	University	68 (25.6)	27 (16.4)	.03*
Family history of HTN	no	72 (27.1)	27 (16.5)	.01*
Family history of HTN	yes	194 (72.9)	137 (83.5)	.01*
Having Diabetes	no	127 (47.7)	64 (38.8)	.07
Having Diabetes	yes	139 (52.3)	101 (61.2)	.07
Having Dyslipidemia	no	44 (16.5)	28 (17)	.89
Having Dyslipidemia	yes	222 (83.5)	137 (83)	.89
Using Metformin	no	150 (56.4)	78 (47.3)	.08
Using Metformin	yes	116 (43.6)	87 (52.7)	.08
Using Sulfonylurea	no	193 (72.6)	105(63.6)	.05
Using Sulfonylurea	yes	73 (27.4)	60 (36.4)	.05
Using Insulin	no	237 (89.1)	147 (89.1)	1
Using Insulin	yes	29 (10.9)	18 (10.9)	1
Using β-blockers	no	174 (66.7)	107 (66)	.92
Using β-blockers	yes	87 (33.3)	55 (34)	.92
Using ACEIs/ARBs	no	142 (53.40	92 (55.8)	.69
Using ACEIs/ARBs	yes	124 (46.6)	73 (44.2)	.69
Using Diuretics	no	229 (86.1)	152 (92.1)	.06
Using Diuretics	yes	37 (13.9)	13 (7.9)	.06
Using CCBS	no	231 (87.5)	145 (87.9)	1
Using CCBS	yes	33 (12.5)	20 (12.1)	1
Severe anxiety symptoms	no	240 (90.2)	76 (46.1)	<.001*
Severe anxiety symptoms	yes	26 (9.38)	89 (53.9)	<.001*
Severe insomnia symptoms	no	219 (82.3)	60 (36.4)	<.001*
Severe insomnia symptoms	yes	47 (17.7)	105 (63.6)	<.001*
Severe perceived stress symptoms	no	90 (33.8)	20(12.1)	<.001*
Severe perceived stress symptoms	yes	176 (66.2)	145 (87.9)	<.001*

Predictors for severe depressive symptoms

The multivariate binary logistic regression model for severe depressive symptoms included age, education, employment status, family history; diabetes, metformin; sulfonylurea; severe anxiety; severe insomnia, and severe stress. In the final model, only age, employment, having diabetes, severe anxiety, and severe insomnia showed a significant association with severe depression. Severe depression was associated with younger age (<55 years) aOR (3.15 (1.829-5.41), P < 0.001), unemployment aOR (2.15 (1.15-4.00), P = 0.01), diabetes aOR (1.81(1.09-3.02), P = 0.02), having severe anxiety aOR (6.40(3.64-11.28), P < 0.001) and having severe insomnia aOR (4.73 (2.85-7.82), P < 0.001). Table 3

Table 3.

Independent correlates of severe depression based on logistic regression analysis.

	B	Wald	Exp(B)	95% CI	P-value
Age below 55 years	1.146	17.139	3.146	1.83-5.41	<.001*
Unemployed	.765	5.855	2.149	1.15-4.00	<.01*
Having diabetes	.594	5.239	1.812	1.09-3.02	<.02*
Having severe anxiety	1.857	41.320	6.403	3.64-11.28	<.001*
Having severe insomnia	1.553	36.450	4.726	2.85-7.82	<.001*

Multivariate binary regression with depression as dependent variable. Depression severity was assessed using Patient Health Questionnaire (PHQ-9) with a cut-off value of 14.

*P < 0.05

Discussion

The present study aimed at investigating whether chronic medications and other patient-related factors are associated with severe depressive symptoms. We report that chronic medications are not associated with severe depressive symptoms: however, we report that younger age (<55 years), unemployment, having diabetes, having severe anxiety, and severe insomnia were associated with severe depressive symptoms.

There are a number of underlying mechanisms suggesting the potential role of antihypertensives in depression. This could include mechanisms involving inflammation,³⁸ neurotransmission³⁹ and others.⁴⁰

The association between antihypertensive use and mental health outcomes is emerging and controversial.^40,41 In our study, no association was found between antihypertensive medications and depression. Several studies focused on the association of β-blockers with depression yielded inconsistent results. For instance, some observational studies demonstrated a positive association between the use of β-blockers and depression.^42,43 Similar to our study, other observational studies did not report such an association. In one multicentre prospective study extending for 12 months, there was no difference in depression scores between β-blocker users and non-users.⁴⁴ In addition, a recent large population-based study did not report any positive association between β-blockers and depression.⁹

This controversy is not only related to β-blockers, as some studies reported that calcium channel blockers (CCB) may be associated with depression and anxiety.⁴⁵ This is supported by clinical assessment from a large hospital database with a follow-up for five years that concluded that the use of CCB is associated with increased risk of mood disorders.⁴⁶ On the other hand, a recent study on elderly patients treated for hypertension found that the use of CCB along with selective serotonin reuptake inhibitor improves depression and cognitive decline seen in elderly patients.⁴⁷

In the present study, antihypertensive medications were not associated with depression. This can be explained based on the cross-sectional study design that did not allow measuring of longitudinal changes of depression i.e., the depression scores in the current study were not measured before and after the antihypertensive therapy. Additionally, the study sample recruited herein was different, depressive symptoms reported by the patients are an outcome of a complex interplay between their underlying medical conditions, environmental exposures and stressors and ethnicity.^48,49 Our sample comprised Jordanian patients with diabetes and dyslipidemia who are receiving different chronic medications such as metformin and statins that could have overlapping effects on depression.^40,50

Another possible explanation of the results is the antihypertensive medication subtype, for example, depression has been related to propranolol, a lipophilic β-blocker, while other β-blockers were not associated with depression.^42,44 Furthermore, the diagnosis or screening of depression across the different studies could yield differences in the results, as while some studies used validated and reliable screening tools,⁴¹ others entirely relied on the use of antidepressants as a proxy for a depression diagnosis.^42,44

Chronic depression can also affect the medication use in hypertension; for example, chronic depression could lead to a chronic activation of the hypothalamus-pituitary-adrenal axis, thus counteracting the effects of antihypertensives.⁵¹

Our findings revealed that having diabetes, having severe anxiety, and having severe insomnia were associated with severe depressive symptoms. The risk of major depression is doubled in people with type 2 diabetes mellitus (T2DM), compared with the general population.⁵² Depressive symptoms are associated with negative behaviours that could predispose to diabetes; inversely, diabetes is associated with depression based on the hormonal and inflammatory basis.⁵³

Our findings demonstrated that severe anxiety and insomnia are independently associated with severe depressive symptoms.

Patients with hypertension are at higher risk of developing mental health challenges, compared to their healthy peers.⁵⁴ Although the relationship between insomnia, anxiety, and depression is strong, nevertheless, the complete underlying mechanisms are not established yet. Existing literature points to the role of interacting social, psychological, and biological factors.⁵⁵

Study limitations

Although the current research has several strengths, such as the sample size; the inclusion criteria and the validated scales, nevertheless, some limitations should be considered. The study subjects were not assessed for psychiatric diagnoses; however, the study used reliable and validated scales to measure all the psychiatric outcomes. However, the cross-sectional design did not allow for measuring longitudinal changes prior and after medication use. Moreover, the sample size per each antihypertensive class was inconsistent.

Conclusions

In this study conducted in Jordan, severe depressive symptoms were not associated with antihypertensive medications or other drugs used by hypertensive patients. Instead, age, diabetes, anxiety, and insomnia were the primary correlates of depression in this patient population.

Footnotes

Acknowledgements

The authors would like to thank Nour, Yasmina, and Suzi for their support.

Authors contribution

Inclusion as a co-author, as required by the International Committee of Medical Journal Editors: have made substantial contributions to the conception or design of the work (Omar Salem Gammoh, Abdelrahim Alqudah, Hanan Abu shaikh) ; or the acquisition, analysis, or interpretation of data for the work (Hanan Abu shaikh , Abdel-Ellah Al-Shudifat, Omar Salem Gammoh) ; AND the drafting the work(Omar Salem Gammoh, Abdelrahim Alqudah) or revising it critically for important intellectual content (Omar Salem Gammoh, Abdel-Ellah Al-Shudifat); AND give their final approval of the version to be published (Omar Salem Gammoh, Abdelrahim Alqudah , Hanan Abu shaikh , Abdel-Ellah Al-Shudifat); AND agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (Omar Salem Gammoh).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded by Yarmouk University (Grant number 2/2023).

ORCID iD

Omar Salem Gammoh

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Severe depressive symptoms in patients with hypertension: Are antihypertensive medications implicated?

Abstract

Objective

Methods

Results

Conclusion

Keywords

Introduction

Methods

Study design and participants

Inclusion criteria

Exclusion criteria

Data collection

The study instrument

Covariates

Chronic medications

Anxiety assessment

Insomnia assessment

Perceived stress assessment

Outcome variable: Depression

Statistical analysis

Results

Response rate

Characteristics of the participants

Factors associated with severe depressive symptoms

Predictors for severe depressive symptoms

Discussion

Study limitations

Conclusions

Footnotes

Acknowledgements

Authors contribution

Declaration of conflicting interests

Funding

ORCID iD

References