Review Article
Drugs 40 (6) 792-799, 1990 0012-6667/90/0012-0792/$04.00/0 © Adis International Limited All rights reserved. DRUG03409
Antihypertensive Medications and Depression Mark H. Beers and Leigh J. Passman Department of Medicine, Division of Geriatric Medicine, University of California at Los Angeles, Los Angeles, California, USA
Contents
Summary ....................................................................................................................................792 I. The Common Signs and Symptoms of Depression .............................. .............................793 2. The Pharmacological Treatment of Hypertension and its Relationship to the Development of Depression ............................................................................................... 793 3. Specific Antihypertensive Drugs .......................................................................................... 794 3.1 Reserpine .................................................................................................................. .......794 3.2 a-Methyldopa ... .. ............................................... .............................................................. 795 3.3 Guanethidine ............................................................ .......................................................795 3,4 Clonidine ......................................................................................................................... 795 3.5 {3-Blockers ........................................................................................................................ 795 3.6 Diuretics .......................................................................................................................... 796 3.7 Calcium Channel Blockers ....... ...................................................................................... 796 3.8 Angiotensin Converting Enzyme (ACE) Inhibitors ...................................................... 796 3.9 Other Agents ......................................................... .............................. .............................797 4. Conclusions ............................................................................................................................ 797
Summary
The association between antihypertensive medications and depression has been recognised for over 40 years. More recently, our understanding of the role of neurotransmitters in the aetiology of depression has helped us understand how antihypertensive drugs cause depression. Biogenic amine depletion is now believed to underlie the organic nature of depression, and many of the drugs used to treat hypertension interfere with this system. There is now compelling evidence that both reserpine and a-methyldopa can induce or worsen depression through their actions on the central nervous system. {3-Blockers have also been implicated, but the data supporting the link between these drugs and depression are not as certain. Guanethidine, clonidine, hydralazine, andprazosin appear to pose little risk in ·causing depression, although rare occurrences have been reported. Diuretics, calcium channel blockers, and angiotensin converting enzyme (ACE) inhibitors appear to have the lowest association with depression and are therefore the drugs of choice when depression is a risk. Physicians should know which drugs introduce. the risk of causing or worsening depression. The wide array of medications now available to treat hypertension offers alternatives that pose low risk. All patients receiving medication to treat hypertension should be evaluated periodically for depression, and if depression occurs, medication should be suspected as playing a role in its aetiology.
Antihypertensive Medications and Depression
1. The Common Signs and Symptoms 0/ Depression Depression is a common illness. In its more severe forms the disease may be life-threatening; however, even in its milder forms, depression robs people of the pleasure of living, destroys relationships and careers, and has a morbidity which is both physical and mental. Unfortunately, the physician sometimes plays an unwjtting role in causing depression as a consequence ·of medication prescription: medicines used to control hypertension are frequent culprits. G.K. Chesterton aptly wrote, The trouble about always trying to preserve the health of the body is that it is so difficult to do without destroying the health of the mind.' The prevalence of depression in the general population has been estimated at 3% (Whitlock & Evans 1976), and between 2 and 13% of older patients suffer from depression (Salzman & van der Kolk 1984). In a review of Medicaid data of over 140 000 patients, approximat~ly 10% of all recipients received tricyclic antidepressants during the 2year study period (A vorn et al. 1986). Depression probably occurs with even greater frequency in populations suffering from chronic disease, especially those to whom medications are prescribed; in one study, a group ofhype~ensive patients were 3 times more likely than non hypertensive patients to suffer from major depression (Rabkin et al. 1983). Broadly defined, depression is an alter~tion of mood characterised by feelings of hopelessness, despair, guilt, self-reproach and sadness, often with associated sleep disturbances, anorexia and suicidal . thoughts and actions. The more severe and classic presentations are not qifficult to diagnose; however, milder and less typical cases occur frequently, in which only selected features appear such as lack of energy, loss of sexual interest, shortened attention span, increased irritability, or decreased pleasure. In the elderly, depression may ptesent as confusion or dementia. Such cases often go unnoticed by the physician though they have serious consequences for patients. Iatrogenic depression,
793
caused or exacerbated by medication, should be considered as a cause of this common disease.
2. The Pharmacological Treatment 0/ Hypertension and its Relationship to the Development 0/ Depression Hypertension, like depression, is common: 18% of a general population record blood pressure greater than l60/95mm Hg (Itskovitz et al. 1977). In fact, even the psychiatrist can expect 15% of his patients to be hypertensive (Sandifer 1987). However, while the value of treating many diseases is in doubt, many studies have shown that the treatment of hypertension decreases mortality and morbidity (Larochelle et al. 1986; Working Group on Hypertension in the Elderly 1986). Thus, it is not surprising that monitoring and treating hypertension is one of the most important tasks of general internists, family practitioners, and cardiologists. Physicians often try to treat hypertension by suggesting weight loss, dietary alteration, and increased activity, but pharmacological medication is the mainstay of antihypertensive therapy. Although the relationship between antihypertensive medications and depression has been suspected for over 40 years, our increasing understanding of the role of neurotransmitters in the aetiology of depression arid our increased awareness of the central actions of a;ntihypertensive medications make the mechariisms of this interaction more easily comprehensible. Of all the medications that physicians prescnbe, those used to trecit hypertension should be niost suspect as causing or worsening depression. Knowing the pharmacological profiles of antihype·rterisive medications will help clinicianschooSe those less likely to induce or worsen depression. Biogenic amine depletion is now believed to underlie the organic nature of depression (Schildkraut 1965). Altered levels of serotonin (5~hydroxytrypt amine), dopamine, and noradrenaline (norepinephrine) are thought to be present in many persons suffering from depression. Other biological theories otdepression suggest an imbalance between cholinergic and adrenergic systems (Jan-
794
owsky et al. 1972). Thus, medications such .as monoamine oxidase inhibitors and tricyclic antidepressants, which directly affect these systems, are effective in treating depression. It is not surprising, therefore, that antihypertensive medications, which interfere with the sympathetic nervous system and with neurotransmitter levels, might induce depression (Whitlock & Evans 1976). It has been known for over 30 years that reserpine decreases levels of serotonin in the brain (Snaith 1976), and for just as long reserpine has been known to be a powerful inducer of depression. The curious effect that tricyclic antidepressants antagonise the antihypertensive effects of guanethidine and clonidine (Thornton 1979) suggests that medications used to treat hypertension and depression may sometimes act on common receptors or interacting pathways and feedback loops. Also, as described below, medications with peripheral action and less penetration into the central nervous system (eNS) seem to be less likely to cause depression. Regardless of theory, if the actual incidence of depression as a side effect of antihypertensive therapy were low, our concern would only be of academic interest. Unfortunately, such side effects are not rare, and the true incidence of milder forms of depression is probably underestimated by the epidemiological methods used to examine this problem. In studies that have used questionnaires, interviews, and chart reviews, investigators have found prevalence rates of depression among hypertensive patients of 30% or higher (Bant 1974; Huapaya & Ananth 1980; Wheatley et al. 1975), which is significantly different from normotensive control groups (Rabkin et al. 1983). The elderly are affected even more often, with some authors claiming that more than 50% of elderly patients receiving antihypertensive drugs have some depression of affect (Salzman & Shader 1979). Most studies have not specifically addressed sedation, sexual dysfunction, and other more subtle signs of depression in their analyses. Any effect on mood may also undermine compliance with drug treatment for hypertension.
Drugs 40 (6) 1990
3. Specific Antihypertensive Drugs 3.1 Reserpine Even before DSM-III criteria and research tools for studying depression, it became evident to clinicians that reserpine caused depression. In the 1950s the first publications suggesting the link between this drug and affective disorders appeared. In the early 1970s the data on the association of reserpine and depression were reviewed (Goodwin et al. 1972). Analysis showed a very high correlation between reserpine use and depression; 20% of the 725 patients studied showed clinical depression, with 7% said to have 'severe' depression. The incidence seemed to be dose related, with a higher occurrence when doses above 0.25 mgjday were used (Hoffman 1981). These researchers and others have noted that those patients with a previous history of depression are most likely to be come depressed while taking this drug. Reserpine has been associated with decreased energy, crying spells, lassitude, hopelessness, indecisiveness, lethargy, agitation and insomnia with great frequency (Salzman & Shader 1978). 'Some experts have stated that anxiety, lack of guilt and lack of self-deprecation are special features in the depression caused by reserpine (Bernstein & Kaufman 1960; Goodwin et al. 1972). These differences in clinical manifestation have led to the claim that the depression caused by reserpine may be distinguishable from the more common endogenous depression and that it might in fact not be depression at all. There are experts who have said that the characteristic psychomotor retardation and sedation caused by this drug is distinct from true depression (Mendels & Frazer 1974), and others (Widmer 1985) have argued that reserpine has been maligned and should be considered a drug of choice in many hypertensive patients. The majority of experts, however, make convincing arguments as to the high frequency and sev~rity of depression induced by reserpine. The disagreement over definition does not alter the patient's suffering from altered mood and performance. Thus, reserpine is now rarely recommended for the treatment of hypertension and is particularly worrisome both in
795
Antihypertensive Medications and Depression
those with a previous history of depression and in the elderly.
3.2 a-Methyldopa a-Methlydopa is widely used to treat hypertension, although its popularity is waning. Although we have had clinical experience with this drug for over 25 years, interestingly, the drug's mechanism of action in treating hypertension is not clear. Though it reduces peripheral catecholamine synthesis by inhibiting dopamine decarboxylase, this is probably not its mechanism of action (Paykel et al. 1982). Central effects are probably more important through depletion of serotonin and dopamine (Henning 1969; Henning & Van Zweiten 1968). That a-methyldopa penetrates the CNS and has some central activity is not in doubt. It is sedating, and this is its most common side effect. The sedation may be severe, leading to an inability to concentrate so profound as to compromise cognition (Adler 1974). Such severe sedation may be misdiagnosed as depression or dementia. The incidence of true depression, though less common than that of sedation, is also high. The incidence ranges from 3.7% (Widmer 1985) to nearly 10% (Ananth & Ghadirian 1980), with higher doses more likely to cause depression. Additionally, people taking a-methyldopa or reserpine are less likely to respond to conventional antidepressant treatment (Akiskal 1982). The elderly are even more susceptible to the depressive effects of amethyldopa (Davidson 1971). There appears to be less controversy over the role of a-methyldopa in inducing depression than for reserpine, and most experts suggest avoiding this drug in patients with a previous history of affective disorders (Whitlock & Evans 1976). 3.3 Guanethidine There is little evidence that guanethidine causes depression with any great frequency. This is not surprising since the drug's major mode of action is peripheral, depressing the function of postgan-
glionic adrenergic nerves; it passes poorly through the blood-brain barrier (Widmer 1985). Although some authors note an incidence of depression well above the norm in patients taking guanethidine (Prichard et al. 1968), most have found only rare occurrences clearly related to the drug. Thus, although guanethidine may occasionally cause or exacerbate depression, it is much less likely to do so than many other medications used to treat hypertension. 3.4 Clonidine Clonidine has both central and peripheral activity. It blocks a2-adrenergic receptors in the periphery and stimulates a-adrenergic receptors centrally (Widmer 1985). Patients report centrally mediated side effects such as sedation, sleep disturbances and nightmares, but depression is not characteristic of this drug. Although case reports associating clonidineand depression are not uncommon and several authoritative sources list the drug as a cause of depression, published analyses of large groups of patients treated with clonidine show an incidence of depression close to that of the general population, and crossover studies have shown improvement in effect when depressed patients were changed from methyldopa or reserpine to clonidine (Raffos et al. 1973). Another study, comparing reserpine, clonidine and placebo, also supports the low incidence of depression with clonidine (Schwarz et al. 1973).
3.5 {1-Blockers ,8-Blockers are widely used today for many illnesses other than hypertension: they affect heart rate, cardiac contractility, pulmonary bronchodilation, skeletal muscle activity, plasma renin levels and myriad other systems. Even their antihypertensive effectiveness is a combination of multiple mechanisms. All {1-blockers penetrate the CNS, though less lipophilic agents, such as atenolol and nadolol, penetrate much less than propranolol (Gengo et al. 1988). Fatigue occurs as a side effect with all {1-blockers in approximately 20% of users
796
(Cruickshank & Prichard 1988a) and may be a result of peripheral effects as well as central ones. Propranolol is sedating and has been shown to cause confusional states and nightmares; it is thus centrally active. As early as 1967, researchers suspected a relationship between depression and the use of propranolol (Waal 1967). Case series have also substantiated tl\e role of fj-blockers in depression (Pollack et al. 1985). Although some authors have reported an incidence of depression as high as 50% when doses were high (Waal 1967), other authors have found no evidence that fj-blockers lead to depression (Medical Reserach Council Working Party on Mild to Moderate Hypertension 1981). Recently, a large population was studied using Medicaid data: 23% of those patients taking a fjblocker also used an antidepressant, compared with 15% or less for those on other antihypertensive medications - a difference that was statistically significant (A vorn et al. 1986). The controversy over the relative role of fjblockers in causing depression is not yet settled. There are still many experts who claim that this class of drugs can be used safely in patients suffering from depression (Cruickshank & Prichard 1988b), although accumulating evidence suggests that {3-blockerscan lead to depression. And although atenolol and nadolql pass less readily through the bIOOd-br:in barrier, there is only minimal evidence that t ey cause iless depression than propranolol (McNei et al. 1982). 3.6 Diuretics Diuretics ate the most commonly chosen treatment for mild to moderate hypertension and are among the most commonly prescribed medications. There are no data to support a significant effect of these medications on the CNS. Although there have been case reports of thiazide-induced depression (Okada 1985), the evidence is not strong, and most authors agree that depression or apathetic behaviour occurs only when electrolyte disturbances develop. Otherwise it appears that these medications have little or no effect on mood.
Drugs 40 (6) 1990
3.7 Calcium Channel Blockers Some calcium channel blockers cross the bloodbrain barrier and are active within the CNS; they may even inhibit the release of noradrenaline (Takahashi & Yoshimura ,I 987). However, there is virtually no published evidence suggesting that any of the currently available calcium channel blocking agents cause or worsen depression. Although the widespread use of calcium channel blockers in the treatment of hypertension is relatively recent and our experience with them is still limited, the current literature would suggest that these medications might be good alternatives when trying to avoid sedation or depression. 3.8 Angiotensin Converting Enzyme (ACE) Inhibitors Since the introduction of captopril in 1980, ACE inhibitors have proved useful in the treatment of congestive heart failure and hypertension (Kostis 1988a). Although efficacious and well tolerated, ACE inhibitors were initially generally regarded as second- or third-line agents in the treatment of essential hypertension (Williams 1988). In recent years, however, attitudes have changed dramatically, and now some experts recommend that ACE inhibitors be considered alongside diuretics and fjblockers as first step treatment for ' mild to moderate hypertension (Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure 1988). This change in attitude, the growing evidence that ACE inhibitors are well tolerated, and the convenience of once-daily dosing available with the newer ACE inhibitors (enalapril and lisinopril) have contributed to a rapid growth in their use. Reduction of circulating angiotensin II and its vasopressor and aldosterone synthesis effects are the principal mechanisms by which ACE inhibitors reduce blood pressure (Goodman et al. 1985; Williams 1988). ACE inhibitors also interfere with a variety of other converting enzyme-dependent pathways, including the degradation of bradykinin (McNeil et al. 1982). In the brain, angiotensin II
797
Antihypertensive Medications and Depression
increases sympathetic discharge, decreases vagal discharge, and stimulates corticotrophin (adenocorticotrophic hormone, ACTH) and vasopressin (antidiuretic hormone, ADH) secretion (Medical Research Council Working Party on Mild to Moderate Hypertension 1981). ACE inhibitors, by reducing angiotensin II, should block these effects, a notion supported by preliminary studies (Glorioso et al. 1987). ACE inhibitors also cross the bloodbrain barrier where they appear to inhibit CSF ACE (Geppetti et al. 1987) and other CNS enzymes such as enkephalinase (Norman et al. 1985). Such effects, which may contribute to the antihypertensive efficacy of these drugs, may also have other CNS consequences which are as .yet unrecognised. Despite their influence on many organ systems, ACE inhibitors are remarkably well tolerated. Their principal adverse effects include hypotension, renal haemodynamic dysfunction, angioedema, and cough (Cruickshank & Prichard 1988b; Nicholls 1987). ACE inhibitors have generally not been associated with depression; in fact, both captopril and enalapril have been reported to produce mood elevation in patients with existing depression (Cohen et al. 1984; Zubenko & Nixon 1984). These researchers have postulated that mood elevation could be secondary to alteration in CNS angiotensin II levels or the metabolism of enkephalin or other ACE-dependent neu~opeptides. Mood elevation has not been reported in patients who were not previously depressed (Callender et al. 1983), but ACE inhibitors may cause other CNS reactions including increased alertness (Olajide & Lader 1985). A few studies have compared the 'well-being' and 'quality oflife' of hypertensive patients treated with ACE inhibitors and other agents (Croog et al. 1986; Kostis 1988a). In one study, patients treated with captopril had an improvement in well-being and work performance not seen with a-methyldopa and propranolol (Callender et al. 1983). However, such findings may reflect avoidance of side effects such as decreased energy, impotence; and depression rather than any intrinsic pharmacological euphoria (Kostis 1988b).
3.9 Other Agents Depression is reported as a side effect with every medication used to treat hypertension. Although hydralazine and prazosin are usually included on the lists of medications known to cause depression, there is only scanty evidence that they do so with any great frequency (Colucci 1982; Paykel et al. 1982). In most studies the incidence approaches that expected for the general population. Other a-blocking agents, such as indoramin, probably have effects similar to prazosin.
4. Conclusions It is often difficult for physicians to accept that the drugs given to control illness might also cause harm. However, there are strong data to show that many medications used to treat hypertension cause or worsen depression, although the exact incidence and prevalence of iatrogenic depression may not be as bad as some have stated. Although the research literature sometimes presents conflicting results, such discrepancies are understandable given the methodological differences used and ·the difficulties inherent in such clinical studies. Despite some problems with the literature, there is now considerable information on theantihypertensive medications that increase thy risk of causing or exacerbating depression. Rese~ine and amethyldopa pose the greatest risk and should be avoided in anyone susceptible to dep'ression. Some controversy remains about ,a-blockers; but given the many other available therapies, thesr medications should probably be avoided when d~pression is a risk. The safest alternatives appear 10 be thiazide diuretics, calcium channel blockers, i, and ACE inhibitors. Guanethidine, clonidine, hydralazine and prazosin are probably safe as well, ~lthough they may not be the drugs of choice whenither¢ is a risk of depression. No one suggests that antihypertensive medications not be used; however, as with ~ny potentially toxic medication, they must be used I, with caution. The physician must know whether . ~ patient has previously suffered from depression, and if so
798
should avoid those drugs with the highest likelihood of reactivating or worsening the disease. At follow-up visits, patients should be checked for depression with directed questions about mood, sadness, pleasure, energy level, sleep, sexuality, relationships and work achievement. In the elderly, both the patient and family should be queried about forgetfulness, confusion and attention. If depression is found, medications should be suspected as the cause and should be tapered or stopped one at a time. Whenever antihypertensive medication is started or changed, the physician must have a high index of suspicion for depression and must be aware of the insidious onset of depression as well as its serious implications to the well-being of the patient.
References Adler S. Methyldopa-induced decrease in mental activity. Journal of the American Medical Association 230: 1428-1429, 1974 Akiskal H. Factors associated with incomplete recovery in primary depressive illness. Journal of Clinical Psychiatry 43: 266- ' 271, 1982 Ananth J, Ghadirian AM. Drug-induced mood disorders. International Pharmacopsychiatry 15: 59-73, 1980 Avorn J, Everitt D, Weiss S. Increased antidepressant use in patients prescribed P-blockers. Journal of the American Medical Association 255: 357-360, 1986 Bant W. Do antihypertensive drugs really cause depression? Proceedings of the Royal Society of Medicine 67:' 920-922, 1974 Bernstein S, Kaufman MR. A psychological analysis of apparent depression following rauwolfia therapy. Journal of Mt Sinai Hospital 27: 525, 1960 Callender JS, Hodsman GP, Hutcheson MJ, et al. Mood changes during captopril therapy for hypertension: a double-blind pilot study. Hypertension 5: 111-90-93, 1;983 Cohen LM, Anderson G, White RF, ,et al. Enalapril and hypertension. American Journal ofPsycliiatry 141 : 1012-1013, 1984 Colucci WS. Alpha-adrenergic receptbr blockade with prazocin. Annals of Internal Medicine 97: 67-77, 1982 Croog SH, Levine S, Testa MA. The Ieffects of antihypertensive therapy on the quality oflife. NeW England Journal of Medicine 314: 1657-1664, 1986 Cruickshank JM, Prichard BNC. Adverse reactions. In Betablockers in clinical practice, p. 792, Churchill Livingston, Edinburgh, 1988a Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, pp. 812-813, Churchill Livingston, Edinburgh, 1988b Davidson W. Drug hazards in the elderly. British Journal of Hospital Medicine 6: 83, 1971 ! Gengo FM, Fagan SC, de Padova A, et al. The effect of betablockers on mental performance in older hypertensive patients. Archives of Internal Medicine 148: 779-784, 1988 Geppetti P, Spillantini MG, Frilli S, jet al. Acute oral captopril inhibits angiotensin converting e~zyme activity in human cerebrovascular fluid. Journal of Hypertension 5: 151-154, 1987 Glorioso N, Dessi-Fulgheri P, Alagn~ S, et al. Angiotensin converting enzyme inhibition reduces !ACTH release due to hypoglycemia. Clinical and Experimental Hypertension Research (Part A) A9(2&3): 665-670, 1987
Drugs 40 (6) 1990
Goodman AG, Gilman LS, Rail TW, Murad F (Eds) The pharmacological basis of therapeutics, p.649, MacMillan Publishing Company, New York, 1985 Goodwin FK, Ebert MH, Bunney WE. Mental effects of reserpine in man: a review: In Shader RI (Ed.) Psychiatric complications of medical drugs, pp. 73-101, Raven Press, New York, 1972 Henning M. Studies on the mod.e of action of alpha methyldopa. Acta Physiologica Scandinavica S322: 3-37, 1969 Henning M, Van Zweiten PA. Central hypotensive effect of alphamethyldopa. Journal of Pharmacy and Pharmacology 20: 409-417, 1968 Hoffman W. ·The behavioral side effects of the antihypertensive agents. American Family Physician 23: 213-216, 1981 Huapaya L, Ananth J. Depression associated with hypertension: a review. Psychiatric Journal of the University of Ottawa 5: 58-62, 1980 Itskovitz HS, Kochar MS, Anderson AJ, Rimm AA. Patterns of blood pressure in Milwaukee. Journal of the American Medical Association 238: 864, 1977 Janowsky DS, EI-YousefK, Davis M, Sekerke HJ. A cholinergicadrenergic hypothesis of mania and depression. Lancet 2: 632, 1972 Joint National Committee on Det~ction, Evaluation and Treatment of High Blood Pressure. 1988 report. Archives ofInternal Medicine 148: 1023-1038, 1988 Kostis JB. Angiotensin converting enzyme inhibitors. I. Pharmacology. American Heart Journal 116: 1580-1591, 1988a Kostis JB. Angiotensin converting enzyme inhibitors. II. Clinical use. American Heart Journal 116: 1591-1605, 1988b Larochelle P,Bass MJ, Birkett NH, De Champlain J, Myers MG. Recommendations from the Consensus Cqnference on Hypertension in the Elderly. Canadian Medical Association Journal 135: 741-745, 1986 McNeil G. Shaw P, Dock D. Substitution of atenolol for propranolol in a case of propranolol related depression. American Journal of Psychiatry 139: 1187-1188, 1982 Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hyperten~ion. Lancet 2: 539543, 1981 Mendels J, Frazer A. Brain biogenic amine depletion and mood. Archives of General Psychiatry. 30: 447,1974 Nicholls MG. Side effects and metabolic effects of convertingenzyme inhibitors. Clinical Experimental ! Hypertension Research (Part A ) A9(2&3): 653-664, 1987 Norman JA, Autry WL, Barbaz BS. Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of [met )-enkephalin-arg6_phe 7 by inhibiting its degradation in mouse brain. Molecular Pharmacology 28: 521-526, 1985 Okada F. Depression after treatment with tli'iazide diuretics for hypertension. American Journal of Psychiatry 142: 1101-1102, 1985 Olajide D, Lader M. Psychotropic effects ofenalapril maleate in normal volunteers. Psychopharmacology (Berlin) 86: 374-376, 1985 Paykel ES, Fleminger R, Watson JP. psychiatric side effects of antihypertensive drugs other than reserpine. Journal of Clinical Psychopharmacology 2: 14-39, 1982 Pollack · MH, Rosenbaum JF, Cassem NH. Propranolol and depression revisited: three cases and a review. Journal ofNervous and Mefltal Disease 173: 118-119, 1985 Prichard BeN, · Johnston AW, et al. Bethani~ine, guanethidine, and methyldopa in the treatment of hypertension: a withinpatient comparison. British Medical Journal I: 135, 1968 Rabkin JG, Charles E, Kass F. Hyperten~ion and DSM-III depres~ion in psychiatric outpatients. American Journal of Psychiatry 140: 1072- 1074, 1983 I Raftos J, Bauer GE, Lewis RG, et al. Clonidine in the treatment
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of severe hypertension. Medical Journal of Australia I: 786793, 1973 Salzman C, Shader R. Depression in the elderly. II. Possible drug etiologies: differential diagnostic criteria. Journal of the American Geriatrics Society 26: 303-308, 1978 Salzman C, van der Kolk B. Treatment of depression. In Salzman C (Ed.) Clinical geriatric psychopharmacology, pp.77-115, McGraw-Hili, New York, 1984 Sandifer M. The hypertensive psychiatric patient: pharmacologic problems. Journal of Clinical Psychiatry 39: 700-702, 1987 Schildkraut JJ. The catecholamine hypothesis of affective disorder: a review of supporting evidence. American Journal of Psychiatry 122: 509-522, 1965 Schwarz D, Michel D, Strian F. Depressive reaktionen unter antihypertensive behandlung. Archiv fur Psychiatria und Nervenkrankheiten 218: 41-50, 1973 Snaith RP. Hypotensive drugs in the treatment of depression. British Journal of Clinical Pharmacology 3 (Suppl. I): 73-74, 1976 Takahashi H, Yoshimura M. The central nervous system and effective antihypertensive effects of a calcium channel blocker. Journal of Cardiovascular Pharmacology 10 (Suppl): 129-133, 1987 Thornton WE. Tricyclic antidepressants and cardiovascular drug interactions. American Family Physician 20: 97-99, 1979
Waal HJ. Propranolol-induced depression. British Medical Journal 2: 50, 1967 Wheatley D, Balter M, Levine J, et al. Psychiatric aspects of hypertension. British Journal of Psychiatry 127: 327-336, 1975 Whitlock FA, Evans LEJ. Drugs and depression. Drugs 15: 5371, 1976 Widmer R. Reserpine: the maligned antihypertensive drug. Journal of Family Practice 20 (I): 81-83, 1985 Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. New England Journal of Medicine 319: 15171525, 1988 Working Group on Hypertension in the Elderly. Statement on hypertension in the elderly. Journal of the American Medical Association 256: 70-74, 1986 Zubenko GS, Nixon RA. Mood-elevating effect of captopril in depressed patients. American Journal of Psychiatry 141: 110Ill, 1984
Correspondence and reprints: Dr Mark H. Beers, University of California at Los Angeles, Department of Medicine, Division of Geriatric Medicine, A-671 Factor Building, 10833 LeConte Avenue, Los Angeles, CA 90024-1687, USA.
University of Malta Pharmacy Department in association with The Parliamentary Secretariat for Care for the Elderly
1st Symposium on Drugs in the Elderly Date: 16-20 March 1991 Venue: Malta For further information please contact: Prof. A. Serracino Inglott Department of Pharmacy University of Malta Msida MALTA
Drugs 40 (6) 792-799, 1990 0012-6667/90/0012-0792/$04.00/0 © Adis International Limited All rights reserved. DRUG03409
Antihypertensive Medications and Depression Mark H. Beers and Leigh J. Passman Department of Medicine, Division of Geriatric Medicine, University of California at Los Angeles, Los Angeles, California, USA
Contents
Summary ....................................................................................................................................792 I. The Common Signs and Symptoms of Depression .............................. .............................793 2. The Pharmacological Treatment of Hypertension and its Relationship to the Development of Depression ............................................................................................... 793 3. Specific Antihypertensive Drugs .......................................................................................... 794 3.1 Reserpine .................................................................................................................. .......794 3.2 a-Methyldopa ... .. ............................................... .............................................................. 795 3.3 Guanethidine ............................................................ .......................................................795 3,4 Clonidine ......................................................................................................................... 795 3.5 {3-Blockers ........................................................................................................................ 795 3.6 Diuretics .......................................................................................................................... 796 3.7 Calcium Channel Blockers ....... ...................................................................................... 796 3.8 Angiotensin Converting Enzyme (ACE) Inhibitors ...................................................... 796 3.9 Other Agents ......................................................... .............................. .............................797 4. Conclusions ............................................................................................................................ 797
Summary
The association between antihypertensive medications and depression has been recognised for over 40 years. More recently, our understanding of the role of neurotransmitters in the aetiology of depression has helped us understand how antihypertensive drugs cause depression. Biogenic amine depletion is now believed to underlie the organic nature of depression, and many of the drugs used to treat hypertension interfere with this system. There is now compelling evidence that both reserpine and a-methyldopa can induce or worsen depression through their actions on the central nervous system. {3-Blockers have also been implicated, but the data supporting the link between these drugs and depression are not as certain. Guanethidine, clonidine, hydralazine, andprazosin appear to pose little risk in ·causing depression, although rare occurrences have been reported. Diuretics, calcium channel blockers, and angiotensin converting enzyme (ACE) inhibitors appear to have the lowest association with depression and are therefore the drugs of choice when depression is a risk. Physicians should know which drugs introduce. the risk of causing or worsening depression. The wide array of medications now available to treat hypertension offers alternatives that pose low risk. All patients receiving medication to treat hypertension should be evaluated periodically for depression, and if depression occurs, medication should be suspected as playing a role in its aetiology.
Antihypertensive Medications and Depression
1. The Common Signs and Symptoms 0/ Depression Depression is a common illness. In its more severe forms the disease may be life-threatening; however, even in its milder forms, depression robs people of the pleasure of living, destroys relationships and careers, and has a morbidity which is both physical and mental. Unfortunately, the physician sometimes plays an unwjtting role in causing depression as a consequence ·of medication prescription: medicines used to control hypertension are frequent culprits. G.K. Chesterton aptly wrote, The trouble about always trying to preserve the health of the body is that it is so difficult to do without destroying the health of the mind.' The prevalence of depression in the general population has been estimated at 3% (Whitlock & Evans 1976), and between 2 and 13% of older patients suffer from depression (Salzman & van der Kolk 1984). In a review of Medicaid data of over 140 000 patients, approximat~ly 10% of all recipients received tricyclic antidepressants during the 2year study period (A vorn et al. 1986). Depression probably occurs with even greater frequency in populations suffering from chronic disease, especially those to whom medications are prescribed; in one study, a group ofhype~ensive patients were 3 times more likely than non hypertensive patients to suffer from major depression (Rabkin et al. 1983). Broadly defined, depression is an alter~tion of mood characterised by feelings of hopelessness, despair, guilt, self-reproach and sadness, often with associated sleep disturbances, anorexia and suicidal . thoughts and actions. The more severe and classic presentations are not qifficult to diagnose; however, milder and less typical cases occur frequently, in which only selected features appear such as lack of energy, loss of sexual interest, shortened attention span, increased irritability, or decreased pleasure. In the elderly, depression may ptesent as confusion or dementia. Such cases often go unnoticed by the physician though they have serious consequences for patients. Iatrogenic depression,
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caused or exacerbated by medication, should be considered as a cause of this common disease.
2. The Pharmacological Treatment 0/ Hypertension and its Relationship to the Development 0/ Depression Hypertension, like depression, is common: 18% of a general population record blood pressure greater than l60/95mm Hg (Itskovitz et al. 1977). In fact, even the psychiatrist can expect 15% of his patients to be hypertensive (Sandifer 1987). However, while the value of treating many diseases is in doubt, many studies have shown that the treatment of hypertension decreases mortality and morbidity (Larochelle et al. 1986; Working Group on Hypertension in the Elderly 1986). Thus, it is not surprising that monitoring and treating hypertension is one of the most important tasks of general internists, family practitioners, and cardiologists. Physicians often try to treat hypertension by suggesting weight loss, dietary alteration, and increased activity, but pharmacological medication is the mainstay of antihypertensive therapy. Although the relationship between antihypertensive medications and depression has been suspected for over 40 years, our increasing understanding of the role of neurotransmitters in the aetiology of depression arid our increased awareness of the central actions of a;ntihypertensive medications make the mechariisms of this interaction more easily comprehensible. Of all the medications that physicians prescnbe, those used to trecit hypertension should be niost suspect as causing or worsening depression. Knowing the pharmacological profiles of antihype·rterisive medications will help clinicianschooSe those less likely to induce or worsen depression. Biogenic amine depletion is now believed to underlie the organic nature of depression (Schildkraut 1965). Altered levels of serotonin (5~hydroxytrypt amine), dopamine, and noradrenaline (norepinephrine) are thought to be present in many persons suffering from depression. Other biological theories otdepression suggest an imbalance between cholinergic and adrenergic systems (Jan-
794
owsky et al. 1972). Thus, medications such .as monoamine oxidase inhibitors and tricyclic antidepressants, which directly affect these systems, are effective in treating depression. It is not surprising, therefore, that antihypertensive medications, which interfere with the sympathetic nervous system and with neurotransmitter levels, might induce depression (Whitlock & Evans 1976). It has been known for over 30 years that reserpine decreases levels of serotonin in the brain (Snaith 1976), and for just as long reserpine has been known to be a powerful inducer of depression. The curious effect that tricyclic antidepressants antagonise the antihypertensive effects of guanethidine and clonidine (Thornton 1979) suggests that medications used to treat hypertension and depression may sometimes act on common receptors or interacting pathways and feedback loops. Also, as described below, medications with peripheral action and less penetration into the central nervous system (eNS) seem to be less likely to cause depression. Regardless of theory, if the actual incidence of depression as a side effect of antihypertensive therapy were low, our concern would only be of academic interest. Unfortunately, such side effects are not rare, and the true incidence of milder forms of depression is probably underestimated by the epidemiological methods used to examine this problem. In studies that have used questionnaires, interviews, and chart reviews, investigators have found prevalence rates of depression among hypertensive patients of 30% or higher (Bant 1974; Huapaya & Ananth 1980; Wheatley et al. 1975), which is significantly different from normotensive control groups (Rabkin et al. 1983). The elderly are affected even more often, with some authors claiming that more than 50% of elderly patients receiving antihypertensive drugs have some depression of affect (Salzman & Shader 1979). Most studies have not specifically addressed sedation, sexual dysfunction, and other more subtle signs of depression in their analyses. Any effect on mood may also undermine compliance with drug treatment for hypertension.
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3. Specific Antihypertensive Drugs 3.1 Reserpine Even before DSM-III criteria and research tools for studying depression, it became evident to clinicians that reserpine caused depression. In the 1950s the first publications suggesting the link between this drug and affective disorders appeared. In the early 1970s the data on the association of reserpine and depression were reviewed (Goodwin et al. 1972). Analysis showed a very high correlation between reserpine use and depression; 20% of the 725 patients studied showed clinical depression, with 7% said to have 'severe' depression. The incidence seemed to be dose related, with a higher occurrence when doses above 0.25 mgjday were used (Hoffman 1981). These researchers and others have noted that those patients with a previous history of depression are most likely to be come depressed while taking this drug. Reserpine has been associated with decreased energy, crying spells, lassitude, hopelessness, indecisiveness, lethargy, agitation and insomnia with great frequency (Salzman & Shader 1978). 'Some experts have stated that anxiety, lack of guilt and lack of self-deprecation are special features in the depression caused by reserpine (Bernstein & Kaufman 1960; Goodwin et al. 1972). These differences in clinical manifestation have led to the claim that the depression caused by reserpine may be distinguishable from the more common endogenous depression and that it might in fact not be depression at all. There are experts who have said that the characteristic psychomotor retardation and sedation caused by this drug is distinct from true depression (Mendels & Frazer 1974), and others (Widmer 1985) have argued that reserpine has been maligned and should be considered a drug of choice in many hypertensive patients. The majority of experts, however, make convincing arguments as to the high frequency and sev~rity of depression induced by reserpine. The disagreement over definition does not alter the patient's suffering from altered mood and performance. Thus, reserpine is now rarely recommended for the treatment of hypertension and is particularly worrisome both in
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Antihypertensive Medications and Depression
those with a previous history of depression and in the elderly.
3.2 a-Methyldopa a-Methlydopa is widely used to treat hypertension, although its popularity is waning. Although we have had clinical experience with this drug for over 25 years, interestingly, the drug's mechanism of action in treating hypertension is not clear. Though it reduces peripheral catecholamine synthesis by inhibiting dopamine decarboxylase, this is probably not its mechanism of action (Paykel et al. 1982). Central effects are probably more important through depletion of serotonin and dopamine (Henning 1969; Henning & Van Zweiten 1968). That a-methyldopa penetrates the CNS and has some central activity is not in doubt. It is sedating, and this is its most common side effect. The sedation may be severe, leading to an inability to concentrate so profound as to compromise cognition (Adler 1974). Such severe sedation may be misdiagnosed as depression or dementia. The incidence of true depression, though less common than that of sedation, is also high. The incidence ranges from 3.7% (Widmer 1985) to nearly 10% (Ananth & Ghadirian 1980), with higher doses more likely to cause depression. Additionally, people taking a-methyldopa or reserpine are less likely to respond to conventional antidepressant treatment (Akiskal 1982). The elderly are even more susceptible to the depressive effects of amethyldopa (Davidson 1971). There appears to be less controversy over the role of a-methyldopa in inducing depression than for reserpine, and most experts suggest avoiding this drug in patients with a previous history of affective disorders (Whitlock & Evans 1976). 3.3 Guanethidine There is little evidence that guanethidine causes depression with any great frequency. This is not surprising since the drug's major mode of action is peripheral, depressing the function of postgan-
glionic adrenergic nerves; it passes poorly through the blood-brain barrier (Widmer 1985). Although some authors note an incidence of depression well above the norm in patients taking guanethidine (Prichard et al. 1968), most have found only rare occurrences clearly related to the drug. Thus, although guanethidine may occasionally cause or exacerbate depression, it is much less likely to do so than many other medications used to treat hypertension. 3.4 Clonidine Clonidine has both central and peripheral activity. It blocks a2-adrenergic receptors in the periphery and stimulates a-adrenergic receptors centrally (Widmer 1985). Patients report centrally mediated side effects such as sedation, sleep disturbances and nightmares, but depression is not characteristic of this drug. Although case reports associating clonidineand depression are not uncommon and several authoritative sources list the drug as a cause of depression, published analyses of large groups of patients treated with clonidine show an incidence of depression close to that of the general population, and crossover studies have shown improvement in effect when depressed patients were changed from methyldopa or reserpine to clonidine (Raffos et al. 1973). Another study, comparing reserpine, clonidine and placebo, also supports the low incidence of depression with clonidine (Schwarz et al. 1973).
3.5 {1-Blockers ,8-Blockers are widely used today for many illnesses other than hypertension: they affect heart rate, cardiac contractility, pulmonary bronchodilation, skeletal muscle activity, plasma renin levels and myriad other systems. Even their antihypertensive effectiveness is a combination of multiple mechanisms. All {1-blockers penetrate the CNS, though less lipophilic agents, such as atenolol and nadolol, penetrate much less than propranolol (Gengo et al. 1988). Fatigue occurs as a side effect with all {1-blockers in approximately 20% of users
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(Cruickshank & Prichard 1988a) and may be a result of peripheral effects as well as central ones. Propranolol is sedating and has been shown to cause confusional states and nightmares; it is thus centrally active. As early as 1967, researchers suspected a relationship between depression and the use of propranolol (Waal 1967). Case series have also substantiated tl\e role of fj-blockers in depression (Pollack et al. 1985). Although some authors have reported an incidence of depression as high as 50% when doses were high (Waal 1967), other authors have found no evidence that fj-blockers lead to depression (Medical Reserach Council Working Party on Mild to Moderate Hypertension 1981). Recently, a large population was studied using Medicaid data: 23% of those patients taking a fjblocker also used an antidepressant, compared with 15% or less for those on other antihypertensive medications - a difference that was statistically significant (A vorn et al. 1986). The controversy over the relative role of fjblockers in causing depression is not yet settled. There are still many experts who claim that this class of drugs can be used safely in patients suffering from depression (Cruickshank & Prichard 1988b), although accumulating evidence suggests that {3-blockerscan lead to depression. And although atenolol and nadolql pass less readily through the bIOOd-br:in barrier, there is only minimal evidence that t ey cause iless depression than propranolol (McNei et al. 1982). 3.6 Diuretics Diuretics ate the most commonly chosen treatment for mild to moderate hypertension and are among the most commonly prescribed medications. There are no data to support a significant effect of these medications on the CNS. Although there have been case reports of thiazide-induced depression (Okada 1985), the evidence is not strong, and most authors agree that depression or apathetic behaviour occurs only when electrolyte disturbances develop. Otherwise it appears that these medications have little or no effect on mood.
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3.7 Calcium Channel Blockers Some calcium channel blockers cross the bloodbrain barrier and are active within the CNS; they may even inhibit the release of noradrenaline (Takahashi & Yoshimura ,I 987). However, there is virtually no published evidence suggesting that any of the currently available calcium channel blocking agents cause or worsen depression. Although the widespread use of calcium channel blockers in the treatment of hypertension is relatively recent and our experience with them is still limited, the current literature would suggest that these medications might be good alternatives when trying to avoid sedation or depression. 3.8 Angiotensin Converting Enzyme (ACE) Inhibitors Since the introduction of captopril in 1980, ACE inhibitors have proved useful in the treatment of congestive heart failure and hypertension (Kostis 1988a). Although efficacious and well tolerated, ACE inhibitors were initially generally regarded as second- or third-line agents in the treatment of essential hypertension (Williams 1988). In recent years, however, attitudes have changed dramatically, and now some experts recommend that ACE inhibitors be considered alongside diuretics and fjblockers as first step treatment for ' mild to moderate hypertension (Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure 1988). This change in attitude, the growing evidence that ACE inhibitors are well tolerated, and the convenience of once-daily dosing available with the newer ACE inhibitors (enalapril and lisinopril) have contributed to a rapid growth in their use. Reduction of circulating angiotensin II and its vasopressor and aldosterone synthesis effects are the principal mechanisms by which ACE inhibitors reduce blood pressure (Goodman et al. 1985; Williams 1988). ACE inhibitors also interfere with a variety of other converting enzyme-dependent pathways, including the degradation of bradykinin (McNeil et al. 1982). In the brain, angiotensin II
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Antihypertensive Medications and Depression
increases sympathetic discharge, decreases vagal discharge, and stimulates corticotrophin (adenocorticotrophic hormone, ACTH) and vasopressin (antidiuretic hormone, ADH) secretion (Medical Research Council Working Party on Mild to Moderate Hypertension 1981). ACE inhibitors, by reducing angiotensin II, should block these effects, a notion supported by preliminary studies (Glorioso et al. 1987). ACE inhibitors also cross the bloodbrain barrier where they appear to inhibit CSF ACE (Geppetti et al. 1987) and other CNS enzymes such as enkephalinase (Norman et al. 1985). Such effects, which may contribute to the antihypertensive efficacy of these drugs, may also have other CNS consequences which are as .yet unrecognised. Despite their influence on many organ systems, ACE inhibitors are remarkably well tolerated. Their principal adverse effects include hypotension, renal haemodynamic dysfunction, angioedema, and cough (Cruickshank & Prichard 1988b; Nicholls 1987). ACE inhibitors have generally not been associated with depression; in fact, both captopril and enalapril have been reported to produce mood elevation in patients with existing depression (Cohen et al. 1984; Zubenko & Nixon 1984). These researchers have postulated that mood elevation could be secondary to alteration in CNS angiotensin II levels or the metabolism of enkephalin or other ACE-dependent neu~opeptides. Mood elevation has not been reported in patients who were not previously depressed (Callender et al. 1983), but ACE inhibitors may cause other CNS reactions including increased alertness (Olajide & Lader 1985). A few studies have compared the 'well-being' and 'quality oflife' of hypertensive patients treated with ACE inhibitors and other agents (Croog et al. 1986; Kostis 1988a). In one study, patients treated with captopril had an improvement in well-being and work performance not seen with a-methyldopa and propranolol (Callender et al. 1983). However, such findings may reflect avoidance of side effects such as decreased energy, impotence; and depression rather than any intrinsic pharmacological euphoria (Kostis 1988b).
3.9 Other Agents Depression is reported as a side effect with every medication used to treat hypertension. Although hydralazine and prazosin are usually included on the lists of medications known to cause depression, there is only scanty evidence that they do so with any great frequency (Colucci 1982; Paykel et al. 1982). In most studies the incidence approaches that expected for the general population. Other a-blocking agents, such as indoramin, probably have effects similar to prazosin.
4. Conclusions It is often difficult for physicians to accept that the drugs given to control illness might also cause harm. However, there are strong data to show that many medications used to treat hypertension cause or worsen depression, although the exact incidence and prevalence of iatrogenic depression may not be as bad as some have stated. Although the research literature sometimes presents conflicting results, such discrepancies are understandable given the methodological differences used and ·the difficulties inherent in such clinical studies. Despite some problems with the literature, there is now considerable information on theantihypertensive medications that increase thy risk of causing or exacerbating depression. Rese~ine and amethyldopa pose the greatest risk and should be avoided in anyone susceptible to dep'ression. Some controversy remains about ,a-blockers; but given the many other available therapies, thesr medications should probably be avoided when d~pression is a risk. The safest alternatives appear 10 be thiazide diuretics, calcium channel blockers, i, and ACE inhibitors. Guanethidine, clonidine, hydralazine and prazosin are probably safe as well, ~lthough they may not be the drugs of choice whenither¢ is a risk of depression. No one suggests that antihypertensive medications not be used; however, as with ~ny potentially toxic medication, they must be used I, with caution. The physician must know whether . ~ patient has previously suffered from depression, and if so
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should avoid those drugs with the highest likelihood of reactivating or worsening the disease. At follow-up visits, patients should be checked for depression with directed questions about mood, sadness, pleasure, energy level, sleep, sexuality, relationships and work achievement. In the elderly, both the patient and family should be queried about forgetfulness, confusion and attention. If depression is found, medications should be suspected as the cause and should be tapered or stopped one at a time. Whenever antihypertensive medication is started or changed, the physician must have a high index of suspicion for depression and must be aware of the insidious onset of depression as well as its serious implications to the well-being of the patient.
References Adler S. Methyldopa-induced decrease in mental activity. Journal of the American Medical Association 230: 1428-1429, 1974 Akiskal H. Factors associated with incomplete recovery in primary depressive illness. Journal of Clinical Psychiatry 43: 266- ' 271, 1982 Ananth J, Ghadirian AM. Drug-induced mood disorders. International Pharmacopsychiatry 15: 59-73, 1980 Avorn J, Everitt D, Weiss S. Increased antidepressant use in patients prescribed P-blockers. Journal of the American Medical Association 255: 357-360, 1986 Bant W. Do antihypertensive drugs really cause depression? Proceedings of the Royal Society of Medicine 67:' 920-922, 1974 Bernstein S, Kaufman MR. A psychological analysis of apparent depression following rauwolfia therapy. Journal of Mt Sinai Hospital 27: 525, 1960 Callender JS, Hodsman GP, Hutcheson MJ, et al. Mood changes during captopril therapy for hypertension: a double-blind pilot study. Hypertension 5: 111-90-93, 1;983 Cohen LM, Anderson G, White RF, ,et al. Enalapril and hypertension. American Journal ofPsycliiatry 141 : 1012-1013, 1984 Colucci WS. Alpha-adrenergic receptbr blockade with prazocin. Annals of Internal Medicine 97: 67-77, 1982 Croog SH, Levine S, Testa MA. The Ieffects of antihypertensive therapy on the quality oflife. NeW England Journal of Medicine 314: 1657-1664, 1986 Cruickshank JM, Prichard BNC. Adverse reactions. In Betablockers in clinical practice, p. 792, Churchill Livingston, Edinburgh, 1988a Cruickshank JM, Prichard BNC. Beta-blockers in clinical practice, pp. 812-813, Churchill Livingston, Edinburgh, 1988b Davidson W. Drug hazards in the elderly. British Journal of Hospital Medicine 6: 83, 1971 ! Gengo FM, Fagan SC, de Padova A, et al. The effect of betablockers on mental performance in older hypertensive patients. Archives of Internal Medicine 148: 779-784, 1988 Geppetti P, Spillantini MG, Frilli S, jet al. Acute oral captopril inhibits angiotensin converting e~zyme activity in human cerebrovascular fluid. Journal of Hypertension 5: 151-154, 1987 Glorioso N, Dessi-Fulgheri P, Alagn~ S, et al. Angiotensin converting enzyme inhibition reduces !ACTH release due to hypoglycemia. Clinical and Experimental Hypertension Research (Part A) A9(2&3): 665-670, 1987
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Goodman AG, Gilman LS, Rail TW, Murad F (Eds) The pharmacological basis of therapeutics, p.649, MacMillan Publishing Company, New York, 1985 Goodwin FK, Ebert MH, Bunney WE. Mental effects of reserpine in man: a review: In Shader RI (Ed.) Psychiatric complications of medical drugs, pp. 73-101, Raven Press, New York, 1972 Henning M. Studies on the mod.e of action of alpha methyldopa. Acta Physiologica Scandinavica S322: 3-37, 1969 Henning M, Van Zweiten PA. Central hypotensive effect of alphamethyldopa. Journal of Pharmacy and Pharmacology 20: 409-417, 1968 Hoffman W. ·The behavioral side effects of the antihypertensive agents. American Family Physician 23: 213-216, 1981 Huapaya L, Ananth J. Depression associated with hypertension: a review. Psychiatric Journal of the University of Ottawa 5: 58-62, 1980 Itskovitz HS, Kochar MS, Anderson AJ, Rimm AA. Patterns of blood pressure in Milwaukee. Journal of the American Medical Association 238: 864, 1977 Janowsky DS, EI-YousefK, Davis M, Sekerke HJ. A cholinergicadrenergic hypothesis of mania and depression. Lancet 2: 632, 1972 Joint National Committee on Det~ction, Evaluation and Treatment of High Blood Pressure. 1988 report. Archives ofInternal Medicine 148: 1023-1038, 1988 Kostis JB. Angiotensin converting enzyme inhibitors. I. Pharmacology. American Heart Journal 116: 1580-1591, 1988a Kostis JB. Angiotensin converting enzyme inhibitors. II. Clinical use. American Heart Journal 116: 1591-1605, 1988b Larochelle P,Bass MJ, Birkett NH, De Champlain J, Myers MG. Recommendations from the Consensus Cqnference on Hypertension in the Elderly. Canadian Medical Association Journal 135: 741-745, 1986 McNeil G. Shaw P, Dock D. Substitution of atenolol for propranolol in a case of propranolol related depression. American Journal of Psychiatry 139: 1187-1188, 1982 Medical Research Council Working Party on Mild to Moderate Hypertension. Adverse reactions to bendrofluazide and propranolol for the treatment of mild hyperten~ion. Lancet 2: 539543, 1981 Mendels J, Frazer A. Brain biogenic amine depletion and mood. Archives of General Psychiatry. 30: 447,1974 Nicholls MG. Side effects and metabolic effects of convertingenzyme inhibitors. Clinical Experimental ! Hypertension Research (Part A ) A9(2&3): 653-664, 1987 Norman JA, Autry WL, Barbaz BS. Angiotensin-converting enzyme inhibitors potentiate the analgesic activity of [met )-enkephalin-arg6_phe 7 by inhibiting its degradation in mouse brain. Molecular Pharmacology 28: 521-526, 1985 Okada F. Depression after treatment with tli'iazide diuretics for hypertension. American Journal of Psychiatry 142: 1101-1102, 1985 Olajide D, Lader M. Psychotropic effects ofenalapril maleate in normal volunteers. Psychopharmacology (Berlin) 86: 374-376, 1985 Paykel ES, Fleminger R, Watson JP. psychiatric side effects of antihypertensive drugs other than reserpine. Journal of Clinical Psychopharmacology 2: 14-39, 1982 Pollack · MH, Rosenbaum JF, Cassem NH. Propranolol and depression revisited: three cases and a review. Journal ofNervous and Mefltal Disease 173: 118-119, 1985 Prichard BeN, · Johnston AW, et al. Bethani~ine, guanethidine, and methyldopa in the treatment of hypertension: a withinpatient comparison. British Medical Journal I: 135, 1968 Rabkin JG, Charles E, Kass F. Hyperten~ion and DSM-III depres~ion in psychiatric outpatients. American Journal of Psychiatry 140: 1072- 1074, 1983 I Raftos J, Bauer GE, Lewis RG, et al. Clonidine in the treatment
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of severe hypertension. Medical Journal of Australia I: 786793, 1973 Salzman C, Shader R. Depression in the elderly. II. Possible drug etiologies: differential diagnostic criteria. Journal of the American Geriatrics Society 26: 303-308, 1978 Salzman C, van der Kolk B. Treatment of depression. In Salzman C (Ed.) Clinical geriatric psychopharmacology, pp.77-115, McGraw-Hili, New York, 1984 Sandifer M. The hypertensive psychiatric patient: pharmacologic problems. Journal of Clinical Psychiatry 39: 700-702, 1987 Schildkraut JJ. The catecholamine hypothesis of affective disorder: a review of supporting evidence. American Journal of Psychiatry 122: 509-522, 1965 Schwarz D, Michel D, Strian F. Depressive reaktionen unter antihypertensive behandlung. Archiv fur Psychiatria und Nervenkrankheiten 218: 41-50, 1973 Snaith RP. Hypotensive drugs in the treatment of depression. British Journal of Clinical Pharmacology 3 (Suppl. I): 73-74, 1976 Takahashi H, Yoshimura M. The central nervous system and effective antihypertensive effects of a calcium channel blocker. Journal of Cardiovascular Pharmacology 10 (Suppl): 129-133, 1987 Thornton WE. Tricyclic antidepressants and cardiovascular drug interactions. American Family Physician 20: 97-99, 1979
Waal HJ. Propranolol-induced depression. British Medical Journal 2: 50, 1967 Wheatley D, Balter M, Levine J, et al. Psychiatric aspects of hypertension. British Journal of Psychiatry 127: 327-336, 1975 Whitlock FA, Evans LEJ. Drugs and depression. Drugs 15: 5371, 1976 Widmer R. Reserpine: the maligned antihypertensive drug. Journal of Family Practice 20 (I): 81-83, 1985 Williams GH. Converting-enzyme inhibitors in the treatment of hypertension. New England Journal of Medicine 319: 15171525, 1988 Working Group on Hypertension in the Elderly. Statement on hypertension in the elderly. Journal of the American Medical Association 256: 70-74, 1986 Zubenko GS, Nixon RA. Mood-elevating effect of captopril in depressed patients. American Journal of Psychiatry 141: 110Ill, 1984
Correspondence and reprints: Dr Mark H. Beers, University of California at Los Angeles, Department of Medicine, Division of Geriatric Medicine, A-671 Factor Building, 10833 LeConte Avenue, Los Angeles, CA 90024-1687, USA.
University of Malta Pharmacy Department in association with The Parliamentary Secretariat for Care for the Elderly
1st Symposium on Drugs in the Elderly Date: 16-20 March 1991 Venue: Malta For further information please contact: Prof. A. Serracino Inglott Department of Pharmacy University of Malta Msida MALTA
