Do antihypertensive medicines increase the risk of depression?

A review of the evidence to examine whether exposure to antihypertensive medicines is linked with depression.
Key words: Antihypertensive, depression, risk/benefit, hypertension


For more than 50 years, a link has been made between the use of antihypertensive drugs and the new onset or re-emergence of symptoms of major depression. Since propranolol became available in the 1960s, both anecdotal and, later, more empirical evidence has emerged that antihypertensive drugs of all classes may have some influence on mood disorders and possibly even on the risk of suicide​[1–5]​. The direction of the evidence (increased vs. decreased risk of depression) and expert opinion is mixed, which does not provide much in the way of helpful guidance for prescribers. The majority of antihypertensive prescriptions today are based on guidance from the National Institute for Health and Care Excellence on hypertension​[6]​. This promotes the use of drugs that target the renin–angiotensin system (RAS) — angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) — dihydropyridine calcium channel blockers and thiazide diuretics at the earlier steps of hypertension management, because of their relatively good profiles in reducing cardiovascular events such as stroke and myocardial infarction​[6]​. Other antihypertensive agents, such as beta-blockers and alpha-blockers, have a less favourable risk/benefit ratio and so appear only as adjuncts or where other agents are contraindicated. Other antihypertensive agents, including centrally-acting agents (such as clonidine and α-methyldopa) and vasopressors (such as hydralazine and sodium nitroprusside) are only used in more specialist cases. Nevertheless, there is evidence linking all classes of antihypertensive drugs with depression and other psychological conditions in the clinical literature, with some classes, and especially some agents, making more frequent appearances than others​[7–9]​. This review explores the association and recent evidence, which suggests that the risk of depression — if or where it exists at all — may differ between sub-classes of antihypertensives.

Antihypertensives and depression: a prescribing dilemma

In the late 1960s, just a few years after the first prototype beta-blocker propranolol became available as an antihypertensive drug, the BMJ reported observations of depression in patients taking the drug​[1]​. Even earlier antihypertensives, such as reserpine and α-methyldopa, have also been linked to the development of depressive symptoms​[10,11]​. Observations of adverse effects reported in reserpine users, in particular, formed the basis of the development of the monoamine hypothesis of depression in the 1950s​[12]​. The monoamine hypothesis posits that depression is associated with a deficit of the monoamines serotonin, noradrenaline and dopamine in the central nervous system (CNS), although today it is recognised that this theory likely explains only a part of the underlying pathology of depression. As the armoury of antihypertensive drugs has increased, giving us the wide range of options available in today’s formularies, the question of whether this now very diverse class of drugs influences mood on either a subclinical or clinical level continues to be posed. Over the years, further evidence has emerged supporting arguments that at least some antihypertensive drugs may actually reduce the risk of depression, while others continue to pose an increased risk, or that their influence as a broad class is negligible​[7,8,13–16]​. Two large-scale, prominent trials considered the effect of antihypertensive use on depression and other patient outcomes. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, published in 2012, investigated the effects of intensive versus standard blood pressure control on depression and health-related quality of life in patients with type 2 diabetes mellitus, and found there was no clinically meaningful difference between the two approaches to managing hypertension​[17]​. In 2017, the findings of SPRINT (Systolic Blood Pressure Intervention Trial) were published, which focused on the effect of intensive blood pressure treatment on patient-reported outcomes, concluding that there was no effect of intensive blood pressure reduction on depression​[18]​.

To deliver and receive the best possible person-centred interventions, prescribers and patients will no doubt take an interest in identifying an antihypertensive drug that best meets the patient’s overall needs, including consideration of the adverse effect profile. This may mean that what is recommended for one individual, based on previous experiences or their ability to tolerate certain adverse effects, will not suit another. History of mental health, or risk of depression, should be considered if there is any risk [of mental health conditions/depression] from the antihypertensive drug. However, the question remains: is there a link betweene antihypertensives and depression and, if so, what weight should be applied to this variable when selecting a suitable antihypertensive drug?

Is there a biological basis?

Largely based on observations of changes in mood in patients who were being treated with reserpine to manage their hypertension, the monoamine theory, introduced above, began to emerge in the 1950s and 1960s​[12]​. Reserpine is one of many alkaloids isolated from extracts of the plant Rauvolfia serpentina, and its mode of action as an antihypertensive is understood to be through irreversible blockade of the vesicular monoamine transporters VMAT1 (in neuroendocrine cells) and VMAT2 (in neurons), resulting in the depletion of both central and peripheral sympathetic amines​[19]​. In the 1960s, seminal work by Joseph Schildkraut showed that monoamine depletion, especially of noradrenaline, appeared to be associated with depression​[12]​. Based on the reported observations of several clinicians that patients taking reserpine were more likely to experience symptoms of depression, and taking into consideration reserpine’s presumed mode of action, it was extrapolated that reserpine use was biologically connected with mood disorders, which contributed to the generation of the monoamine hypothesis of depression. However, reserpine is a drug that is associated with a variety of perceived adverse effects and was not well tolerated by many patients at the doses prescribed at the time​[20]​.

Shortly after propranolol became available as an important new development in the management of hypertension, evidence slowly began to emerge that also connected the drug with symptoms of depression​[1,21]​. Propranolol is a non-selective beta-adrenergic antagonist, more commonly known as a beta-blocker, which has lipophilic properties allowing passage across the blood–brain barrier, resulting in both central and peripheral effects​[22]​. Its pharmacology and pharmacodynamic properties are more complex than the class name suggests, but of particular relevance to this review are its weak effects on noradrenaline availability (increased) in the synapses of the CNS and weak blockade of several serotonin receptors, which may impact in some way on arousal and mood​[23,24]​.

The advancement of antihypertensive therapy in the intervening years has seen the rise of numerous other beta-blockers, diuretics, calcium channel blockers and drugs that target the RAS appearing in the British National Formulary and clinical guidelines, but the question of their impact on mood has not been resolved. In contrast with the attempts outlined above to understand the involvement of monoamines, many of the antihypertensives used clinically today are reported to either increase or decrease the risk of depression based, perhaps, on other biological mechanisms​[2]​. Theories have been posed based on genetic differences and neuroinflammatory mechanisms, which remain inconclusive but nevertheless plausible​[25–28]​.

There is mixed evidence for an association between cerebral blood flow and mood in older people. Saper argues that maintaining a systolic blood pressure at or below 120mmHg, as recommended following the results of SPRINT, is insufficient for adequate cerebral perfusion in older people​[29]​. In an epidemiological study, Hildrum et al. found that there is an association between low blood pressure and mood, but a randomised controlled trial by Moonen et al. found no evidence that discontinuing antihypertensives in older people led to any improvement in cognitive function​[30,31]​

A review of the evidence

For this review, 21 articles (see Figure) were identified as exemplars of the range of evidence and opinion available for practitioners to inform their recommendations and shared decision making. Articles were included based on guiding criteria, which were: 1. Articles must be published in English; 2. Articles must report investigation of a possible relationship between use of one or more antihypertensive drugs in humans and any symptoms commonly associated with depression as defined by ICD-10 criteria, either as part of a trial or in routine clinical practice; 3. Studies of any kind reporting primary data or metadata, but not review or opinion articles. Of the 21 studies, 6 explored the association between beta-blockers and depression (including symptoms, formal diagnoses, associated mental health conditions or risk of suicide) and 15 explored the same relationship for 2 or more antihypertensive drugs. The studies were a mixture of systematic reviews of randomised controlled trials with meta-analyses, cohort and case-control studies, cross-sectional and other observational studies. Ten studies concluded that there was no substantial evidence of any association between antihypertensive use, of any class, and depression. Two studies concluded that all of the antihypertensive drugs investigated had a protective effect against depression. One study found dichotomous class effects with drugs divided into “increases risk” and “decreases risk” categories. The remaining 8 studies concluded that there may be an increased risk of depression for one or more of the antihypertensives investigated in the study. These findings are summarised in the Figure​[5,7–9,13–16,32–44]​.

In total, 18 of the studies investigated the association between beta-blockers and depression. Eight of these studies reported an increased risk of new onset or recurrence of a previous diagnosis of depression with beta-blocker use. One study — a cross-sectional study of 3,218 new beta-blocker users — found that the proportion of propranolol users receiving antidepressant prescriptions was 9.5%, several times greater than for any other lipophilic or hydrophilic beta-blocker​[43]​. Two other studies in this group specifically highlighted the more lipophilic beta-blockers as having a notable association with depression, whereas four other studies reported a more general class effect of beta-blockers​[7,9,16,33,41]​. Sørensen et al. reported that, compared with the general population, patients taking lipophilic beta-blockers are at 2.7 times increased risk of mortality associated with suicide in the first 12 months of use, although there are numerous confounding factors in the lipophilic beta-blocker cohort, which may explain at least part of this effect​[5]​. Li et al. conducted a systematic review, followed by a network meta-analysis of five studies involving 263,025 patients, and found that when compared to diuretics, beta-blockers, calcium channel blockers and angiotensin antagonists were all associated with an increased risk of depression​[7]​. It is not clear whether hypertension was the indication for all drugs and therefore there is a possibility that the findings are dependent on other underlying confounders that are also predictors of depression.

Among the ten studies that found no substantial evidence of any increased risk of depression associated with beta-blockers was a large systematic review and meta-analysis by Riemer et al., which identified 285 randomised controlled trials of 24 beta-blockers​[14]​. The authors highlighted that, compared with placebo, reports of fatigue/tiredness and unusual dreams were increased in users of beta-blockers and suggested that these specific adverse effects may, in many cases, be misinterpreted as depression. The authors of at least two other studies also make this point and, given the relative subjectivity of depression scoring and diagnosis, even guided by DSM-5 or ICD-10 criteria, there is likely to be considerable variability in the differential diagnoses between physicians and even, for each physician, between patients​[38,39,45,46]​.

Of the 13 studies that considered calcium channel blockers, 3 reported an increased risk of depression​[7,33,41]​, 2 reported a decreased risk​[8,13]​, and the remainder found no substantial evidence of any impact on the risk of depression. Those reporting a decreased risk found a similar effect for most antihypertensives. Kessing et al. report the findings of a Danish population-based study to investigate 41 antihypertensive drugs, which found that none of the drugs increased the risk of depression, while several individual drugs were associated with a decrease in depression diagnoses or antidepressant use for each category of calcium channel blockers, drugs that target the RAS and beta-blockers (including propranolol)​[8]​.

The risk associated with drugs that target the RAS appears to be inconclusive, and the majority of studies did not find any substantial evidence associating the use of these drugs and depression. Three studies reported a decrease in the risk for both ACEIs and ARBs compared with other agents or placebo​[8,13,33]​, whereas two studies found an increased risk for ARBs​[7,41]​ and three studies reported an increased risk associated with ACEIs​[16,41,42]​. The magnitude of these effects was small but statistically significant in all studies reporting an association.

For diuretics, seven studies did not find substantial evidence of any effect, although one study reported an increased risk of depression​[41]​, with one further study reporting a decreased risk​[13]​.

To summarise, when pooling the findings from a range of published studies, none of the drugs used to treat hypertension appear to be entirely absent of risk for either depression or symptoms that are associated with depression. However, there is a greater body of evidence covering beta-blockers and almost half of these studies associate this class of drugs, and particularly the more lipophilic beta-blockers, with increased risk of depression. We must be extremely cautious when interpreting these findings as there are many other important variables that may have influenced the outcomes of these studies and that, in turn, influence risk prediction for depression based on the published data. Our observations of many of these factors are discussed in more detail later in this article, but it is important to first consider the similarities and differences between the antihypertensive drug classes which may affect the respective depression risk, in addition to how these agents are prescribed to manage hypertension.

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

For the first step of the treatment of hypertension, NICE recommends the use of ACEIs or ARBs in patients aged under 55 years for some categories of patients​[6]​. There is evidence that chronic activation of the RAS may contribute to neuroinflammation, leading to both neurogenic hypertension and increasing risk of psychological and neurological disorders, including depression (where emotion pathways are involved) and dementia​[25,27]​. The arm of the RAS responsible for the proinflammatory effects is known as the classical RAS, which is balanced by the counter-regulatory RAS, which has a neuroprotective role.

In both arms of the RAS, angiotensinogen is cleaved by renin to produce angiotensin I, which in turn is cleaved by ACE to angiotensin II. Through the type 1 angiotensin II receptor (AT1R), angiotensin II promotes vasoconstriction and inflammation, as part of the classical RAS pathway. But in the counter-regulatory RAS pathway, angiotensin II acts through another receptor type, known as the type 2 angiotensin II receptor (AT2R), to promote vasodilation and reduced inflammation. At the same time, angiotensin II is cleaved by ACE2, forming angiotensin-(1-7) peptide, which also promotes vasodilation and reduced inflammation via the Mas receptor​[25]​.

Inhibition of ACE counters the chronic activation of the classical RAS pathway, whereas ARBs target angiotensin II AT1 receptors, thus inhibiting the classical arm of the RAS. Both mechanisms lead to vasodilation, reduced secretion of vasopressin and reduced production and secretion of aldosterone, combining overall to reduce blood pressure. However, it is not clear if the action of ACE inhibitors and ARBs on the peripheral RAS is replicated in the central RAS to exert any neuroprotective effects, although it is known that several of these antihypertensives are active in the CNS (e.g. perindopril, candesartan)​[47,48]​.

Calcium channel blockers

The NICE guideline for hypertension recommends the use of calcium channel blockers in other categories of patients for step 1 of treatment, rather than using an ACEI​[6]​. There is evidence from genetic data that dysfunctional L-type calcium channels are associated with an increased risk of depression and other psychiatric disorders, and that intracellular calcium dysregulation is apparent in depressed patients​[49]​.

Following activation of the voltage-gated calcium channels in the cell membrane, the entry of calcium into the cell is vital for essential cellular processes, including neurotransmitter release, hormone release and gene expression. A dysfunctional calcium channel will disrupt this sensitive signalling, as it may have a lower or higher activation threshold, leading to consequences for the normal functioning of the cell​[26]​. In CNS pathways responsible for mood and emotion, this may manifest as a set of symptoms characterising one or more psychiatric disorders.

This has implications for the use of the groups of drugs known as dihydropyridine calcium channel blockers in patients at risk of or diagnosed with depression, and the prescribing of CCBs has been associated with a decreased risk of depression in some small studies. For many years, despite the more mainstream, evidence-based approach to managing bipolar disorder with lithium and antiepileptics, calcium channel blockers have sometimes been used where tolerability to other agents has been poor​[50]​. Clinical evidence supporting this approach is scant, but recent genetic studies have identified possible connections between L-type calcium channels and the pathology of bipolar disorder​[51–53]​. The effects of Verapamil and diltiazem on depression have been investigated in several studies and it is possible that all calcium channel blockers (dihydropyridines, phenylalkylamines and benzothiazepines) may be associated with changes in psychiatric function, but further studies are needed to explore this relationship​[54]​.


NICE does not recommend thiazide diuretics as part of step one intervention unless one of the first-line options is not tolerated, but this class of drugs is one of the recommended escalation options at step two. There is very little evidence pointing to thiazide diuretics being implicated in depression and the presumed mechanisms of action of thiazides and thiazide-like agents in reducing blood pressure, or their pharmacodynamic properties, are not easily extrapolated to the possible explanations of the underlying pathophysiology of mood disorders. Low-dose thiazide diuretics inhibit the resorption of Na+ and Cl ions by blocking the Na+/Cl transporter in the distal convoluted tubules of the kidney, and this results in a greater loss of water in the urine. The reduced overall volume in the blood vessels reduces outward pressure on the vessel walls, thereby producing an antihypertensive effect​[55]​.


NICE does not recommend the use of beta-blockers before step four of a treatment strategy for resistant hypertension, and only then if the patient is at risk of (or has) hyperkalaemia and would not therefore tolerate spironolactone(6). Beta-blockers have fallen out of favour in the management of hypertension because evidence shows they are less effective than drugs that target the RAS, calcium channel blockers and diuretics at preventing cardiovascular events, although they are more effective than placebo​[56,57]​.

Beta-blockers are competitive antagonists of the adrenaline and noradrenaline binding sites of the beta-adrenergic receptors in the sympathetic nervous system. Some beta-blockers are non-selective and will block all three sub-types of beta receptor, whereas other agents will more selectively block activity at β1, β2 or β3 receptors. The target for beta-blockers in hypertension management is β1 receptors, which are found predominantly in the heart and kidneys​[58]​.

The mechanism by which beta-blockers induce an antihypertensive effect is likely multifactorial. Beta-blockers are known to have negative chrono- and inotropic effects, leading to a reduced cardiac output and therefore possibly reduced pressure on the vessel walls. The action of beta-blockers on the sympathetic nervous system (for those agents that can enter the CNS) and the direct effect of systemic beta-blockers on the kidney leads to a reduction in renin output and a consequent decrease in aldosterone secretion. This causes more Na+ and water to be excreted in the urine, decreasing blood volume and pressure​[59]​.

Beta-blockers have been implicated in depression almost since they were first used more than 50 years ago, although there remains no consensus on whether or not this effect is real. Those beta-blockers that are more lipophilic, such as propranolol, have a greater ability to diffuse through the blood–brain barrier and can therefore enter the CNS more readily compared with hydrophilic beta-blockers, such as atenolol​[60]​. Lipophilic agents are therefore more likely to be associated with central effects such as fatigue, sleep/dream disorders or depression​[61]​. Beta-blockers disrupt rapid eye movement sleep and can therefore cause insomnia, which in turn leads to poor concentration and attention, impaired performance and even mood disturbance during the daytime​[62,63]​. This impact on sleep and disruption to the sleep/wake cycle is the mechanism that some have proposed connects beta-blocker use with reports of depression​[32]​.

Other antihypertensives

Clonidine, α-methyldopa and moxonidine are centrally-acting antihypertensive drugs. Clonidine is an α2-antagonist, suppressing noradrenaline and renin release, and is not routinely used in modern hypertension management because sudden withdrawal can lead to a hypertensive crisis​[64]​. α-methyldopa is also an α2-antagonist and is used, off-label, for managing hypertension in pregnancy, but can cause fluid retention with long-term use​[65]​. Moxonidine causes its antihypertensive effect through activity at the imidazoline receptor I1. It is sometimes, but rarely, used in resistant hypertension or where other antihypertensives are not suitable​[66]​.

Guanethidine is obsolete in modern hypertension management, except in a hypertensive emergency — although other agents are usually preferred. It works by preventing the release of noradrenaline from nerve endings in the sympathetic nervous system and can lead to a rapid antihypertensive effect, but postural hypotension is common​[67]​.

Hydralazine, sodium nitroprusside, minoxidil and nitrates are all vasodilators that have strong and rapid antihypertensive effects. Several other drugs, including sildenafil, tadalafil and ambrisentan, are licensed for the treatment of pulmonary arterial hypertension. All of these agents are initiated only in specialist cases​[68]​.

NICE states that α1-antagonists (e.g. prazosin, doxazosin, alfuzosin) may be introduced at step four in the management of resistant hypertension as an alternative to beta-blockers, or patients with hypertension may be prescribed α1-antagonists for another indication, such as benign prostatic hyperplasia​[69]​. These agents have vasodilator properties and can induce a rapid antihypertensive effect after the first dose. α1-antagonists act by blocking the action of noradrenaline at the α1 adrenergic receptors in the vascular smooth muscle, preventing vasoconstriction.

Consideration of other contributing factors and uncertainties 

It is reported that around 20% of patients with ischaemic heart disease (IHD) have major depression, and many more present with symptoms that are often associated with the condition, such as fatigue or unusual dreams, independent of antihypertensive use​[70]​. These important factors are likely to contribute to the association between antihypertensives and depression, and raise important questions about how depression is diagnosed and underlying causal factors.

The psychological burden of living with long-term illnesses or risk factors can itself be the cause of a patient developing symptoms of depression or anxiety, and many patients will have a history of mood disorders that may re-emerge when triggered by a new or worsening comorbidity, hospitalisation or other factors associated with a change to their quality of life​[71,72]​.

For many years, beta-blockers (especially propranolol) have been used effectively to help patients manage their anxiety by controlling the somatic symptoms associated with sympathetic nervous system activity, such as trembling, tachycardia and sweating. There is a strong, recognised association between anxiety and depression, and these disorders often manifest as comorbidities, which poses a problem when trying to understand the role of beta-blockers in raising the risk of mood disorders when other risk factors are already present​[73]​.

It is also important to acknowledge that depression itself is a predictor of heart disease and stroke, with an increased incidence of hypertension in patients who are depressed​[74–76]​. We are therefore faced with the age-old ‘chicken-and-egg’ problem when we further confound this relationship with treatments to control blood pressure.

Reduced adherence to antihypertensive treatment is recognised to be a predictor of depression and is an important confounding factor that should be controlled wherever possible in studies exploring this relationship​[77]​. Interestingly, depression does not appear to be a predictor of statin intolerance — a treatment for another silent risk factor for IHD​[78]​. What is not clear is whether poor adherence to antihypertensives could be a reliable predictor of depression, although uncontrolled hypertension does appear to have a detrimental effect on depression​[79]​.

There are also limitations to the evidence available to us when trying to understand the relationship between adherence and depression. Although reaching different conclusions, both Li et al. and Riemer et al. reported moderate to considerable heterogeneity between studies, reducing the reliability of their findings​[7,14]​. Earlier in this review, we considered the relatively subjective nature of depression diagnosis and we cannot rule out the likelihood of unintended clinician bias when attempting to differentiate between chronic sleep disorders, for example, and depression. It is also likely that there is some degree of reporting bias and publication bias, which may disproportionately add weight to studies reporting a positive correlation between antihypertensive use and depression​[80]​.

Conclusion and future perspectives

While the relationship between antihypertensive use and depression remains unclear, it is important that clinicians continue to work with patients to manage hypertension, for which there is substantial evidence of increased risk of incident stroke or myocardial infarction. It is prudent to consider the risk of depression for each individual based on their medical history and act accordingly, including the patient in the discussion about their treatment options and taking their personal goals and choices into account. The most effective management of hypertension is likely to be when clinical guidelines are followed, the most appropriate dose is prescribed for the patient, and adverse effects are being monitored.

Further studies that investigate the effects of individual antihypertensives are needed, since the physicochemical and pharmacological properties of agents within each class differ sufficiently that there is varying CNS exposure, a varying degree of specificity of receptor activity and, therefore presumably, varying risk of inducing symptoms associated with depression or other psychiatric conditions. Well-designed prospective trials in primary care could provide useful evidence, and large-scale epidemiological studies with carefully considered co-variables would help to refine understanding of the risk.

  1. 1
    Waal HJ. Propranolol-induced depression. BMJ. 1967;2:50–50. doi:10.1136/bmj.2.5543.50
  2. 2
    Koella WP. CNS-related (side-)effects of ?-Blockers with special reference to mechanisms of action. Eur J Clin Pharmacol. 1985;28:55–63. doi:10.1007/bf00543711
  3. 3
    Beers MH, Passman LJ. Antihypertensive Medications and Depression. Drugs. 1990;40:792–9. doi:10.2165/00003495-199040060-00003
  4. 4
    Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology 1996;7:478–84.
  5. 5
    Sørensen HT, Mellemkjaer L, Olsen JH. Risk of suicide in users of β-adrenoceptor blockers, calcium channel blockers and angiotensin converting enzyme inhibitors. British Journal of Clinical Pharmacology. 2001;52:313–8. doi:10.1046/j.0306-5251.2001.01442.x
  6. 6
    Hypertension in adults: diagnosis and management. National Institute for Health and Care Excellence. 2022. (accessed Aug 2023).
  7. 7
    Li Y, Fan Y, Sun Y, et al. Antihypertensive Drug Use and the Risk of Depression: A Systematic Review and Network Meta-analysis. Front. Pharmacol. 2021;12. doi:10.3389/fphar.2021.777987
  8. 8
    Kessing LV, Rytgaard HC, Ekstrøm CT, et al. Antihypertensive Drugs and Risk of Depression. Hypertension. 2020;76:1263–79. doi:10.1161/hypertensionaha.120.15605
  9. 9
    Ringoir L, Pedersen S, Widdershoven J, et al. Beta-blockers and depression in elderly hypertension patients in primary care. Fam Med 2014;46:447–53.
  10. 10
    Freis ED. Mental Depression in Hypertensive Patients Treated for Long Periods with Large Doses of Reserpine. N Engl J Med. 1954;251:1006–8. doi:10.1056/nejm195412162512504
  11. 11
    alpha-Methyldopa and depression: a clinical study and review of the literature. AJP. 1983;140:534–8. doi:10.1176/ajp.140.5.534
  12. 12
  13. 13
    Simonson W, Han LF, Davidson HE. Hypertension Treatment and Outcomes in US Nursing Homes: Results From the US National Nursing Home Survey. Journal of the American Medical Directors Association. 2011;12:44–9. doi:10.1016/j.jamda.2010.02.009
  14. 14
    Riemer TG, Villagomez Fuentes LE, Algharably EAE, et al. Do β-Blockers Cause Depression? Hypertension. 2021;77:1539–48. doi:10.1161/hypertensionaha.120.16590
  15. 15
    Brownstein DJ, Salagre E, Köhler C, et al. Blockade of the angiotensin system improves mental health domain of quality of life: A meta-analysis of randomized clinical trials. Aust N Z J Psychiatry. 2017;52:24–38. doi:10.1177/0004867417721654
  16. 16
    Cao YY, Xiang X, Song J, et al. Distinct effects of antihypertensives on depression in the real-world setting: A retrospective cohort study. Journal of Affective Disorders. 2019;259:386–91. doi:10.1016/j.jad.2019.08.075
  17. 17
    O’Connor PJ, Narayan KMV, Anderson R, et al. Effect of Intensive Versus Standard Blood Pressure Control on Depression and Health-Related Quality of Life in Type 2 Diabetes. Diabetes Care. 2012;35:1479–81. doi:10.2337/dc11-1868
  18. 18
    Berlowitz DR, Foy CG, Kazis LE, et al. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med. 2017;377:733–44. doi:10.1056/nejmoa1611179
  19. 19
    Yaffe D, Forrest LR, Schuldiner S. The ins and outs of vesicular monoamine transporters. Journal of General Physiology. 2018;150:671–82. doi:10.1085/jgp.201711980
  20. 20
    Saseen J. Pharmacologic management of hypertension. In: Antman E, Sabatine M, eds. Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease. Philadelphia: : W.B. Saunders 2013. 474–489.
  21. 21
    Srinivasan A. Propranolol: A 50-year historical perspective. Ann Indian Acad Neurol. 2019;22:21. doi:10.4103/aian.aian_201_18
  22. 22
    Al-Majed AA, Bakheit AHH, Abdel Aziz HA, et al. Propranolol. Profiles of Drug Substances, Excipients and Related Methodology. 2017;:287–338. doi:10.1016/bs.podrm.2017.02.006
  23. 23
    Tuross N, Patrick R. Effects of propranolol on catecholamine synthesis and uptake in the central nervous system of the rat. J Pharmacol Exp Ther 1986;237:739–45.
  24. 24
    Hoyer D, Clarke D, Fozard J, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 1994;46:157–203.
  25. 25
    Tran S, Kuruppu S, Rajapakse NW. Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia? JAD. 2022;85:943–55. doi:10.3233/jad-215231
  26. 26
    Saddala MS, Lennikov A, Mukwaya A, et al. Discovery of novel L-type voltage-gated calcium channel blockers and application for the prevention of inflammation and angiogenesis. J Neuroinflammation. 2020;17. doi:10.1186/s12974-020-01801-9
  27. 27
    Mowry FE, Biancardi VC. Neuroinflammation in hypertension: the renin-angiotensin system versus pro-resolution pathways. Pharmacological Research. 2019;144:279–91. doi:10.1016/j.phrs.2019.04.029
  28. 28
    Osimo EF, Baxter LJ, Lewis G, et al. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol. Med. 2019;49:1958–70. doi:10.1017/s0033291719001454
  29. 29
    Saper CB. How low can you go? Ann Neurol. 2015;78:665–6. doi:10.1002/ana.24530
  30. 30
    Hildrum B, Mykletun A, Stordal E, et al. Association of low blood pressure with anxiety and depression: the Nord-Trondelag Health Study. Journal of Epidemiology & Community Health. 2007;61:53–8. doi:10.1136/jech.2005.044966
  31. 31
    Moonen JEF, Foster-Dingley JC, de Ruijter W, et al. Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning—the DANTE Study Leiden. JAMA Intern Med. 2015;175:1622. doi:10.1001/jamainternmed.2015.4103
  32. 32
    Agustini B, Mohebbi M, et al. The association of antihypertensive use and depressive symptoms in a large older population with hypertension living in Australia and the United States: a cross-sectional study. J Hum Hypertens. 2020;34:787–94. doi:10.1038/s41371-020-0303-y
  33. 33
    Boal AH, Smith DJ, McCallum L, et al. Monotherapy With Major Antihypertensive Drug Classes and Risk of Hospital Admissions for Mood Disorders. Hypertension. 2016;68:1132–8. doi:10.1161/hypertensionaha.116.08188
  34. 34
    Bornand D, Reinau D, Jick SS, et al. β-Blockers and the Risk of Depression: A Matched Case–Control Study. Drug Saf. 2022;45:181–9. doi:10.1007/s40264-021-01140-5
  35. 35
    Chowdhury EK, Berk M, Nelson MR, et al. Association of depression with mortality in an elderly treated hypertensive population. Int. Psychogeriatr. 2018;31:371–81. doi:10.1017/s1041610218000856
  36. 36
    Gerstman BB, Jolson HM, Bauer M, et al. The incidence of depression in new users of beta-blockers and selected antihypertensives. Journal of Clinical Epidemiology. 1996;49:809–15. doi:10.1016/0895-4356(96)00017-0
  37. 37
    Johansen A, Holmen J, Stewart R, et al. Anxiety and depression symptoms in arterial hypertension: the influence of antihypertensive treatment. The HUNT study, Norway. Eur J Epidemiol. 2011;27:63–72. doi:10.1007/s10654-011-9641-y
  38. 38
    Ko DT. β-Blocker Therapy and Symptoms of Depression, Fatigue, and Sexual Dysfunction. JAMA. 2002;288:351. doi:10.1001/jama.288.3.351
  39. 39
    Michal M, Wiltink J, Lackner K, et al. Association of hypertension with depression in the community. Journal of Hypertension. 2013;31:893–9. doi:10.1097/hjh.0b013e32835f5768
  40. 40
    Ranchord AM, Spertus JA, Buchanan DM, et al. Initiation of β-blocker therapy and depression after acute myocardial infarction. American Heart Journal. 2016;174:37–42. doi:10.1016/j.ahj.2015.11.018
  41. 41
    Shaw RJ, Mackay D, Pell JP, et al. The relationship between antihypertensive medications and mood disorders: analysis of linked healthcare data for 1.8 million patients. Psychol. Med. 2020;51:1183–91. doi:10.1017/s0033291719004094
  42. 42
    Selected Abstracts from Pharmacology 2022. Brit J Clinical Pharma. 2022;89:1226–63. doi:10.1111/bcp.15523
  43. 43
    Thiessen B, Wallace S, Blackburn J, et al. Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch Intern Med 1990;150:2286–90.
  44. 44
    Verbeek DEP, van Riezen J, de Boer RA, et al. A Review on the Putative Association Between Beta-Blockers and Depression. Heart Failure Clinics. 2011;7:89–99. doi:10.1016/j.hfc.2010.08.006
  45. 45
    Buch AM, Liston C. Dissecting diagnostic heterogeneity in depression by integrating neuroimaging and genetics. Neuropsychopharmacol. 2020;46:156–75. doi:10.1038/s41386-020-00789-3
  46. 46
    GOLDBERG D. The heterogeneity of “major depression”. World Psychiatry. 2011;10:226–8. doi:10.1002/j.2051-5545.2011.tb00061.x
  47. 47
    Yamada K, Horita T, Takayama M, et al. Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats. Brain Research. 2011;1421:110–20. doi:10.1016/j.brainres.2011.09.016
  48. 48
    Li N-C, Lee A, Whitmer RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465–b5465. doi:10.1136/bmj.b5465
  49. 49
    Andrade A, Brennecke A, Mallat S, et al. Genetic Associations between Voltage-Gated Calcium Channels and Psychiatric Disorders. IJMS. 2019;20:3537. doi:10.3390/ijms20143537
  50. 50
    Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Update 2009 on the Treatment of Acute Mania. The World Journal of Biological Psychiatry. 2009;10:85–116. doi:10.1080/15622970902823202
  51. 51
    Catterall WA, Perez-Reyes E, Snutch TP, et al. International Union of Pharmacology. XLVIII. Nomenclature and Structure-Function Relationships of Voltage-Gated Calcium Channels. Pharmacol Rev. 2005;57:411–25. doi:10.1124/pr.57.4.5
  52. 52
    Jimerson D, Post R, Carman J, et al. CSF calcium: clinical correlates in affective illness and schizophrenia. Biol Psychiatry 1979;14:37–51.
  53. 53
    Heyes S, Pratt WS, Rees E, et al. Genetic disruption of voltage-gated calcium channels in psychiatric and neurological disorders. Progress in Neurobiology. 2015;134:36–54. doi:10.1016/j.pneurobio.2015.09.002
  54. 54
    Cipriani A, Saunders K, Attenburrow M-J, et al. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development. Mol Psychiatry. 2016;21:1324–32. doi:10.1038/mp.2016.86
  55. 55
    Duarte JD, Cooper-DeHoff RM. Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Review of Cardiovascular Therapy. 2010;8:793–802. doi:10.1586/erc.10.27
  56. 56
    Wiysonge CSU, Bradley HA, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database of Systematic Reviews. 2007. doi:10.1002/14651858.cd002003.pub2
  57. 57
    Khan N, McAlister F. Re-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis. CMAJ 2006;174:1737–42. doi:10.1503/cmaj.060110
  58. 58
    Wong GW, Boyda HN, Wright JM. Blood pressure lowering efficacy of beta-1 selective beta blockers for primary hypertension. Cochrane Database of Systematic Reviews. 2016;2016. doi:10.1002/14651858.cd007451.pub2
  59. 59
    Pucci G, Ranalli MG, Battista F, et al. Effects of β-Blockers With and Without Vasodilating Properties on Central Blood Pressure. Hypertension. 2016;67:316–24. doi:10.1161/hypertensionaha.115.06467
  60. 60
    Guan L, Yang H, Cai Y, et al. ADMET-score – a comprehensive scoring function for evaluation of chemical drug-likeness. Med. Chem. Commun. 2019;10:148–57. doi:10.1039/c8md00472b
  61. 61
    Cojocariu SA, Maștaleru A, Sascău RA, et al. Neuropsychiatric Consequences of Lipophilic Beta-Blockers. Medicina. 2021;57:155. doi:10.3390/medicina57020155
  62. 62
    Kostis JB, Rosen RC. Central nervous system effects of beta-adrenergic-blocking drugs: the role of ancillary properties. Circulation. 1987;75:204–12. doi:10.1161/01.cir.75.1.204
  63. 63
    Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine Reviews. 2002;6:97–111. doi:10.1053/smrv.2002.0186
  64. 64
    Cao C, Lorenz ML, Sojka P, et al. Hypertensive Crisis in a Pediatric Patient Experiencing Clonidine Withdrawal. Case Reports in Pediatrics. 2022;2022:1–4. doi:10.1155/2022/9005063
  65. 65
    Redman CWG, Beilin LJ, Bonnar J. TREATMENT OF HYPERTENSION IN PREGNANCY WITH METHYLDOPA: BLOOD PRESSURE CONTROL AND SIDE EFFECTS. BJOG:An international journal of O&G. 1977;84:419–26. doi:10.1111/j.1471-0528.1977.tb12616.x
  66. 66
    Fenton C, Keating GM, Lyseng-Williamson KA. Moxonidine. Drugs. 2006;66:477–96. doi:10.2165/00003495-200666040-00006
  67. 67
    KADZIELAWA K. MECHANISM OF ACTION OF GUANETHIDINE. British Journal of Pharmacology and Chemotherapy. 1962;19:74–84. doi:10.1111/j.1476-5381.1962.tb01428.x
  68. 68
    Houtchens J, Martin D, Klinger JR. Diagnosis and Management of Pulmonary Arterial Hypertension. Pulmonary Medicine. 2011;2011:1–13. doi:10.1155/2011/845864
  69. 69
    Lepor H. Alpha blockers for the treatment of benign prostatic hyperplasia. Rev Urol 2007;9:181–90.
  70. 70
    Rudisch B, Nemeroff CB. Epidemiology of comorbid coronary artery disease and depression. Biological Psychiatry. 2003;54:227–40. doi:10.1016/s0006-3223(03)00587-0
  71. 71
    Turner J. Emotional dimensions of chronic disease. Western Journal of Medicine. 2000;172:124–8. doi:10.1136/ewjm.172.2.124
  72. 72
    Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry. 2022;9:137–50. doi:10.1016/s2215-0366(21)00395-3
  73. 73
    Kalin NH. The Critical Relationship Between Anxiety and Depression. AJP. 2020;177:365–7. doi:10.1176/appi.ajp.2020.20030305
  74. 74
    Barlinn K, Kepplinger J, Puetz V, et al. Exploring the risk-factor association between depression and incident stroke: a systematic review and meta-analysis. NDT. 2014;:1. doi:10.2147/ndt.s63904
  75. 75
    Davidson K, Jonas BS, Dixon KE, et al. Do Depression Symptoms Predict Early Hypertension Incidence in Young Adults in the CARDIA Study? Arch Intern Med. 2000;160:1495. doi:10.1001/archinte.160.10.1495
  76. 76
    Jonas BS. Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Archives of Family Medicine. 1997;6:43–9. doi:10.1001/archfami.6.1.43
  77. 77
    Eze-Nliam CM, Thombs BD, Lima BB, et al. Depression and Adherence to Antihypertensive Therapy. American Journal of Hypertension. 2008;21:724–5. doi:10.1038/ajh.2008.194
  78. 78
    Bytyçi I, Penson PE, Mikhailidis DP, et al. Prevalence of statin intolerance: a meta-analysis. European Heart Journal. 2022;43:3213–23. doi:10.1093/eurheartj/ehac015
  79. 79
    Wang L, Liu Q, Sun D, et al. Effects of Combination Treatment in Hypertensive Patients with Depression: A Systematic Review and Meta-Analysis of 27 Randomized Controlled Trials. TCRM. 2022;Volume 18:197–211. doi:10.2147/tcrm.s347622
  80. 80
    Luijendijk HJ, Koolman X. The incentive to publish negative studies: how beta-blockers and depression got stuck in the publication cycle. Journal of Clinical Epidemiology. 2012;65:488–92. doi:10.1016/j.jclinepi.2011.06.022
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The Pharmaceutical Journal, PJ, August 2023, Vol 311, No 7976;311(7976)::DOI:10.1211/PJ.2023.1.193972

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