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Transcript of Antidepresivos y Enfermedad Cardiovascular
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Clinical overview
Antidepressant drugs and cardiovascular
pathology: a clinical overview of effectivenessand safety
Taylor D. Antidepressant drugs and cardiovascular pathology: a clinicaloverview of effectiveness and safety.
Objective: To review data examining the relationships betweendepression, antidepressants and cardiovascular disease.Method: Structured searches of PubMed, Medline and Embaseconducted in March 2008.
Results: Depression and cardiovascular disease are closely associatedclinical entities. Depression appears both to cause and worsencardiovascular disease. Cardiovascular disease is in turn associatedwith a high incidence of depression. Depression is associated withincreased mortality in cardiovascular disease, and after myocardialinfarction (MI) and stroke. Many antidepressants have cardiotoxicproperties. Tricyclic drugs are highly cardiotoxic in overdose and mayinduce cardiovascular disease and worsen outcome in establishedcardiovascular disease. Reboxetine, duloxetine and venlafaxine areknown to increase blood pressure. Other antidepressants have neutralor beneficial effects in various cardiovascular disorders.Conclusion: Sertraline, fluoxetine, citalopram, bupropion andmirtazapine appear to be safe to use after MI; the use of sertraline, andresponse to citalopram and mirtazapine may improve mortality.Paroxetine and citalopram appear to be safe to use in patients withestablished coronary artery disease. Limited data suggest that a varietyof antidepressants are effective and safe to use after stroke.
D. Taylor
Pharmacy Department, Maudsley Hospital and Division
of Pharmaceutical Sciences, Kings College, London, UK
Key words: depression; cardiovascular disease;
antidepressants
David Taylor, Pharmacy Department, Chief Pharmacist,
Maudsley Hospital, Denmark Hill, London SE5 8AZ, UK.
E-mail: [email protected]
Accepted for publication July 18, 2008
Clinical recommendations
All patients diagnosed with depression should be closely monitored for other factors (obesity,hypertension, diabetes, physical inactivity, plasma cholesterol) associated with cardiovasculardisease.
All patients with depression should be advised to take steps to reduce behaviours (e.g. high alcoholconsumption, high fat diet, inactivity) associated with cardiovascular disease and, when necessary,receive physical treatments (e.g. antihypertensive or cholesterol-reducing drugs) aimed at reducing
cardiovascular risk. Tricyclic antidepressants should be avoided in patients with or at risk of cardiovascular disease. Developing evidence suggests that certain drugs can be safely used in different cardiovascular
conditions.
Additional comments
The nature and extent of the relationship between depression and cardiovascular disease has yet to befully established.
Conclusions are limited by the dearth or absence of data on the use of many antidepressants incardiovascular disease.
Acta Psychiatr Scand 2008: 118: 434442All rights reservedDOI: 10.1111/j.1600-0447.2008.01260.x
Copyright 2008 The AuthorJournal Compilation 2008 Blackwell Munksgaard
ACTA PSYCHIATRICASCANDINAVICA
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Introduction
Depression and cardiovascular disease are highlyprevalent in all societies and so, if only bycoincidence, the two will frequently occur together,necessitating careful selection of antidepressanttreatment. There is a growing body of evidence
suggesting that depression is associated both withthe development of coronary artery disease andwith increased mortality after myocardial infarc-tion (MI) and stroke (1, 2). Antidepressants show awide range of cardiovascular effects [arrhythmog-enicity, autonomic function changes, reduction inheart variability, hypotension, hypertension andchanges in platelet activity (35)] which are highlylikely to affect cardiovascular morbidity and mor-tality. The cardiovascular effects of individualantidepressants vary considerably and selection ofthe most appropriate drug is of vital importance.
Choice of antidepressant is made difficult by thenumerous cardiovascular effects of antidepressantsand by complex interactions between depression,antidepressant use and cardiovascular mortality.
Aims of the study
To examine the above interactions and makerecommendations for safe and effective use ofantidepressants in different types of cardiovasculardisease.
Material and methodsSearches of Pubmed, Medline and Embase wereundertaken in March 2008 using the followingterms: depression, cardiovascular disease, MI,stroke, antidepressants (as a group and by name),mortality and coronary artery disease. Referencesections of obtained articles were scrutinized forfurther relevant articles. Where available, pub-lished meta-analyses were used in preference toindividual studies so as to reduce the complexity ofthe review.
Results
Depression and cardiovascular disease
There is an established association between depres-sion and the development of cardiovascular diseaseand between depression and cardiovascular mor-tality. The nature and extent of these associationshave yet to be precisely determined, largely becauseof the failure of many studies to account and adjustfor confounding variables such as smoking (6),physical activity (7) and aspects of the metabolic
syndrome (8). An additional limitation to many ofthese studies is the variety of ways in whichdepression was diagnosed. Although manydescribe the occurrence of depression, not allestablished the diagnosis using widely recognizedcriteria.
In a meta-analysis of 10 studies (9) the relative
risk of developing coronary disease in those with ahistory of depression was estimated to be 1.64[95% confidence interval (CI) 1.411.90]. Four ofthese studies controlled for only two major con-founders and six accounted for three. A meta-analysis of 20 studies examining mortality insubjects with coronary heart disease (10) foundthat depressive symptoms afforded a substantiallyincreased risk of death [odds ratio (OR), 2.24; 95%CI 1.373.60] after 2 years. After adjustment forother measured risk factors, the relative risk wasreduced [hazard ratio (HR), 1.76; 95% CI 1.27
2.43] but still statistically significant.The findings of both of these analyses arereflected in the largest meta-analysis published todate (54 studies, 146 538 participants) (11). Therelative risk of developing coronary heart diseasein those with depression was 1.81 (95% CI 1.532.15); relative risk of death due to cardiovascularevents was 1.80 (1.52.15). Adjustment of the latterestimate for the presence of impaired left ventric-ular function resulted in a 48% reduction inestimated relative risk.
A comprehensive and scholarly review of depres-sion and coronary artery disease (12) evaluated the
link between the two entities on seven criteria. Itwas found that i) there was a good evidence of anassociation, that ii) depression was a good predic-tor of coronary artery disease, that iii) there was afair degree of specificity for depression and coro-nary artery disease (i.e. depression predicts thisbetter than other physical outcomes), that iv) therewas general consistency in study outcome, that v)there was a clear doseresponse effect (the worsethe depression, the greater the likelihood of coro-nary artery disease), that vi) the association wasbiologically plausible, but that there was vii)
insufficient evidence to demonstrate that treatmentof depression reduced the likelihood of coronaryartery disease.
These data, taken together, suggest an importantassociation between depression and cardiovasculardisease but do not establish causation. Indeed, it ispossible and valid to conclude that cardiovasculardisease is associated with (and perhaps is acausative factor in) depression. Nonetheless, sev-eral mechanisms have been put forward to explainthe supposed causative link between depressionand cardiovascular disease (13). Perhaps the most
Antidepressant drugs and cardiovascular pathology
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compelling of these is the observation that subjectswith depression show exaggerated platelet reactiv-ity (14) which appears to be related to elevatedplasma levels of platelet factor 4 and b-thrombo-globulin (15). Heart rate variability appears not tobe altered in depression (16).
Depression after MI
Around a third of people become depressed in theyear after suffering an MI (17). Depression worsensoutcome after MI. Frasure-Smith et al. followedup 222 patients for 18 months having screened allsubjects for depression 515 days post-MI (17, 18).After 6 months (17) adjusted HR for death (takinginto account left ventricular dysfunction and pre-vious MI) was 4.29 (95% CI 3.145.44) in thosewho were depressed post-MI. At 18 months (18)adjusted OR for death in depressed subjects was
6.64 (95% CI 1.7625.09).A meta-analysis of 22 studies (6367 MI patients)(19) found that depression was significantly asso-ciated with both all-cause mortality (OR 2.38, 95%CI 1.763.22) and cardiac mortality (OR 2.59, 95%CI 1.773.77). Most included studies adjusted for alarge number of confounding factors. Method ofassessment of depression had no significant effecton estimated risk. Many studies defined depressionas a score of10 on the Beck Depression Inventory(20) but there is evidence that scores of 49 are alsosignificantly associated with increased mortality(21). Depression seems to be linked to reduced
heart rate variability in post-MI patients (22), aknown risk factor for mortality post-MI (23).Depression may also significantly increase mortal-ity in people with unstable angina (24).
Antidepressants after MI
Five studies have evaluated the impact of usingantidepressants after MI (see Table 1). The Sertr-aline Anti-Depressant Heart Attack Trial(SADHAT) (2527) examined the use of sertralinein depressed subjects experiencing MI or unstable
angina. Initial pilot studies suggested that sertra-line was well tolerated (25) and that its use reducedplatelet activation in addition to that afforded byco-administered anti-platelet regimens (26). Themain study (27) compared 186 subjects givensertraline with 183 given placebo over 24 weeks.The use of sertraline was indistinguishable fromplacebo on all surrogate measures of cardiovascu-lar safety and did not increase the incidence ofcardiovascular events. Sertraline was only margin-ally more effective than placebo in treating depres-sion an observation, according to the study
authors, reflecting the brevity and self-limitingnature of a substantial proportion of depressionafter MI.
The Enhancing Recovery in Coronary HeartDisease study (ENRICHD; 28) examined the useof early cognitive behavioural therapy [with addi-tional selective-serotonin reuptake inhibitor (SSRI;
usually sertraline) treatment in severely depressedunresponsive subjects] in 1238 subjects comparedwith 1243 receiving usual care. The study treatmentwas more effective against depression than usualcare but did not effect event-free survival. Antide-pressant use (in either subject group) was associ-ated with a significantly reduced risk of death. Asub-analysis of these antidepressant data (29)suggested that the use of SSRIs was largelyresponsible for this effect: risk of death or recurrentMI was not altered by the use of non-SSRIantidepressants.
In the third and most recent major study (30)[Myocardial Infarction and Depression Interven-tion Trial, (MIND-IT)], 2177 MI patients wereevaluated for depression and randomized to thestudy intervention (mirtazapine vs. placebo, otherantidepressants or no pharmacological treatment)or usual care. The intervention showed noimprovement in depression compared with usualcare and had no effect on cardiac event rate at18 months. Sub-analyses of those receiving antide-pressants in the intervention arm compared withsubjects not receiving antidepressants in the usualcare arm showed no effect, protective or otherwise.
A follow-up analysis (31) revealed that thoseresponding to mirtazapine or citalopram had asignificantly lower rate of mortality than thoseprescribed an antidepressant but not responding.These findings imply that it is response to treat-ment that is protective against future cardiacevents.
Two further, smaller studies have suggested thatfluoxetine (32) and bupropion (33) do not increasecardiovascular risk after MI.
Antidepressants in coronary artery disease
Two prospective studies have addressed the safetyand efficacy of antidepressant treatment in coro-nary artery disease. The Canadian Cardiac Ran-domized Evaluation of Antidepressant andPsychoTherapy Efficacy (CREATE) trial (34) assessed short-term outcome in 284 subjects givencitalopram 2040 mg day, placebo, interpersonaltherapy (IPT) or standard clinical management.Participants had established coronary artery dis-ease defined as evidence of previous MI, previouscardiac revascularization or angiographic evidence
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Table 1. Controlled studies of antidepressants in depression after MI
Trial Design Outcome Conclusions
Strik et al. (32) Randomized double-blind controlled trial of
fluoxetine (2060 mg day) vs. placebo for 925
weeks in depression after first MI (n = 54)
Depression change measured using HAMD-17;
cardiac safety by echocardiography and ECG
Depression diagnosed according to DSM-III-R criteria
Response rate higher for fluoxetine (48%) than
for placebo (26%)
Ventricular stroke volume and QRS interval
decreased in more subjects on fluoxetine than on
placebo. One patient rehospitalized for cardiac
events on fluoxetine, six on placebo.
Cardiac changes on fluoxetine
deemed clinically
insignificant Fluoxetine is
safe and effective post-MI
SADHART (27) Randomized, double-blind trial of sertraline
(50200 mg day) vs. placebo for 24 weeks for
depression following MI (74%) or unstable
angina (26%) (n = 369).
Depression diagnosed according to DSM-IV
Depression change measured using HAM-D
and CGI (98).
Cardiac parameters: left ventricular ejection fraction
(LVEF); ECG changes and number of premature
complexes, cardiac events and death
Sertraline more effective than placebo on CGI but
not HAM-D. Clearer response in more severe
depression. Sertraline did not change baseline
cardiac parameters
Incidence of severe cardiovascular events was
14.5% with sertraline and 22.4% with placebo.
Death occurred in two subjects on sertraline, five
on placebo
Sertraline is safe and
effective post-MI
unstable angina
ENRICHD (28) Randomized, double-blind, controlled trial of treatment
for depression and low perceived social support
(cognitive behavioural therapy, CBT, supplemented, if
necessary, with an SSRI) following MI vs. usual care.
Depression diagnosed according to DSM-IV criteria
Depression change measured using HAMD-17 (99) andBeck Depression Inventory (20). Cardiac safety
evaluated using ECG, Echo, cardiac events and
survival. Average follow-up 29 months.
Of participants, 39.4% had depression only, 26.1% low
social support only, 34.5% depression and low
social support
Intervention had modest effect on depressive
symptoms (mean decrease in BDI 49% vs. 33%).
Intervention had no effect on probability of death,
non-fatal MI or hospitalization for cardiovascular
events.
Antidepressant use (most received sertraline)significantly reduced risk of death or non-fatal MI
(adjusted hazard ratio 0.63, 95% CI 0.460.87)
CBT has no effect on survival
or cardiovascular events
Use of sertraline and other
SSRIs reduces risk of death
and MI
ENRICHD (29) (sub-
analysis of those with
depression)
As above but only those 73.9% with
depression analysed
As above, use of antidepressants in intervention
arm and usual care arm included
Death occurred in 21.5% of those who received an
antidepressant, 26.0% of those who did not
(adjusted HR 0.63, 95% CI 0.430.93)
Risk of recurrent MI also reduced in people on
antidepressants (adjusted HR 0.57, 95%
CI 0.380.87)
Overall, 67.5% received an SSRI (sertraline first
choice in intervention arm), 32.5% received non-
SSRI antidepressant. Of those on SSRIs 49.5%
received sertraline, 28.9% paroxetine, 13.0% flu
oxetine, 7.6% citalopram
SSRIs reduce risk of death in
those depressed after MI.
Rigotti et al. (33) Randomized, double-blind controlled trial of bupropion
(300 mg day) and placebo in smokers hospitalized for
MI, unstable angina, coronary artery bypass graft or
other acute cardiovascular disease (n = 248)
Depression not evaluated. Cardiovascular events
evaluated using number of cardiovascular
events and 1 year survival
Bupropion did not effect 1 year survival
(cardiovascular mortality 0% bupropion, 2%
placebo) or cardiovascular events (16% vs. 14%).
Bupropion safe in smokers
post MI.
MIND-IT (30) Randomized, double-blind trial of antidepressant
treatment (mirtazapine first choice, citalopram second)
vs. usual care in depression following MI (n = 331).
18 month follow-up depression diagnosed according to
ICD-10 criteria. Depression change evaluated with BDI.
Cardiac status by predefined event frequency
(cardiac death, MI, hospitalization, bypass surgery,arrhythmia)
In placebo-controlled sub-study, 47 subjects received
mirtazapine, 44 placebo. Of these, 20 and 26 patients,
respectively, went on to receive citalopram
Intervention had no advantage over usual care on
depression prevalence or severity at 18 months
In the intervention group, 14% suffered a cardiac
event compared with 13% in the usual care group
Use of antidepressants also had no effect on cardiac
event rate [OR 0.84, 95% CI 0.381.84; 14%
(antidepressant) vs. 12% event rate]
Antidepressant treatment had
no effect on depression or
cardiac event rate
MIND-IT (sub-analy-
sis by response to
treatment)
As above but sub-analyses of responders to
antidepressant treatment (50% reduction in
HAM-D or score
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of at least 50% blockage of one or more coronaryartery. Citalopram was more effective againstdepression than placebo but the effect size wassmall (0.33). IPT was no better in treating depres-sion than standard clinic care. Citalopram andplacebo did not differ with respect to effect oncardiac parameters such as blood pressure, heart
rate or ECG change. Of 12 serious cardiovascularevents occurring, six occurred in those receivingcitalopram and six in those given placebo.
In the second study, 81 subjects with coronaryartery disease were randomized to paroxetine 2030 mg day or nortriptyline (plasma level 50150 ng ml). Both drugs were effective in treatingdepression (35) but only nortriptyline affectedcardiac measures: increased heart rate, reducedheart variability and increased cardiac adverseeffects were observed with nortriptyline (36). Par-oxetine appears to reduce platelet activation in
coronary artery disease (37, 38). Nortriptyline hasno effect on platelet activation (37) but reducesheart rate variability (39).
Antidepressants and stroke
Depression is seen in up to 40% of patientssuffering stroke (40) and is associated with wors-ened functional impairment (41, 42) and increasedmortality (HR at 3 years: 1.13, 95% CI 1.061.21)(43).
A meta-analysis of 16 placebo-controlled studiesincluding 1320 patients (44) concluded that antide-
pressants were more effective than placebo intreating poststroke depression (response rates65.18% active treatment; 44.37% placebo). Sertr-aline, fluoxetine, escitalopram and nortriptylinehave also been shown to prevent the emergence ofdepression in stroke patients (4547). The use ofantidepressants seems to not affect recovery ofcognitive or social functioning (4850), but mayreduce risk of death: one study found that 59.2%of patients receiving 12 week poststroke antide-pressants were alive 9 years later compared with36.4% of those receiving placebo (P = 0.03) (51).
Data on the effects of antidepressants on mor-tality poststroke are otherwise limited. In theory,the anti-platelet effect of SSRIs would be expectedto decrease the risk of thrombo-embolic stroke andincrease the risk of haemorrhagic stroke. Theoverall effect on mortality is not known but nostudy has reported an increased risk.
Antidepressants and heart failure
Tricyclic antidepressants are poorly tolerated inpeople with heart failure because of their propen-
sity to cause orthostatic hypotension (5255), anadverse effect observed to be least severe withnortriptyline (53). SSRIs (55, 56) and bupropion(54, 57) (amfebutamone) are not associated withsignificant hypotension, ECG changes or changesin left ventricular function in people with heartfailure.
Cardiotoxicity of antidepressants
The relative acute cardiotoxicity of antidepressantdrugs is suggested by their Fatal Toxicity Index(FTI the number of poisoning deaths per millionprescriptions). Estimates of the FTIs for tricyclicantidepressants as a group range from (meanvalues) 12 (58) to 43 (59, 60), although lofepramineshows uniquely low toxicity [FTI estimated at 1(58), 1.3 (61) and 2.7 (59)]. Monoamine oxidaseinhibitors show mean FTIs in the range 13 (62) to
27 (59) with tranylcypromine by far the most toxic(59, 61). FTIs for SSRIs as a group have beenestimated at 2 (58, 62) and 4.3 (60), although theFTI for SSRI poisonings involving no other drugsis as low as 1 (60). Trazodone shows moderatetoxicity [FTI of around 10 (58, 59, 61)] as doesvenlafaxine [FTI estimated at 18 (60) and 13 (61,63)]. Mirtazapine, reboxetine and mianserin haveestimated FTIs of a magnitude similar to that ofSSRIs (58, 59, 61) although data are relativelylimited. There are no data on duloxetine.
The FTI data need careful interpretation whenconsidering drug-related cardiotoxicity. In tricyclic
overdose, cardiac arrhythmia is probably the mostcommon cause of death (64, 65), although seizuresmake a significant contribution with some individ-ual drugs (66). Neither seems to occur withlofepramine (67). Tricyclics are cardiac sodium(INa) and potassium channel (IKr) antagonists (6870) and prolong QRS and QT intervals, particu-larly in overdose (65) although small effects areseen in normal doses (71). These quinidine-likeeffects on sodium channels seem to account for thehigh incidence of ventricular arrhythmia inoverdose (63). Drugs with similar cardiac actions
may increase mortality when used in patients atrisk of arrhythmia (72) and tricyclics might also beexpected to do so (73). Anticholinergic and alpha-adrenergic effects of tricyclics cause cardiovascularadverse effects (tachycardia, hypotension) at clin-ical doses and in overdose.
The FTI data for SSRIs, mirtazapine, reboxetineand mianserin imply limited acute toxicity of anysort, so suggesting minimal acute cardiotoxicity.These drugs have no or insignificant effects on theECG in normal clinical doses (74) and reports ofarrhythmia or significant ECG changes are extre-
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mely rare. Moclobemide, the only monoamineoxidase inhibitor still in widespread use, seems tohave no effect on cardiac conduction (75). The FTIof trazodone suggests moderate overdose toxicity.Deaths from overdose with trazodone alone arerare (76) but when death occurs, arrhythmia maybe the cause (77, 78).
The reported FTI values for venlafaxine aremore difficult to interpret. These values suggestmoderate acute toxicity and venlafaxine appears toblock cardiac sodium channels (79). However,venlafaxine causes no ECG changes in standarddoses (80) and only very rarely (i.e. at a frequencysimilar to that of SSRIs) causes arrhythmia inoverdose (81, 82). Its higher FTI may be related tothe risk of seizures in overdose (81, 82) or to thepossibility that FTI is sometimes a poor measure oftoxicity. This is best illustrated by the variation inFTI estimated for individual drugs [estimated FTI
for nortriptyline ranges from 1 (60) to 54 (59)].Other factors are thus clearly important and thereis evidence that venlafaxine is prescribed topatients at relatively higher risk of suicide (83, 84).
Other cardiovascular effects
Most tricyclic antidepressants (4) and mirtazapine(85) cause significant orthostatic hypotension innormal clinical doses. Reboxetine (86), duloxetine(87) and venlafaxine (88) are associated with smallincreases in blood pressure. SSRIs have importanteffects on homeostasis and are conclusively linked
to an increased risk of bleeding (89).
Antidepressants and risk of MI
Tricyclic antidepressants reduce heart rate vari-ability (90) and have long been suspected ofincreasing the risk of cardiovascular events, includ-ing MI (91). In a US cohort study of members of ahealth insurance plan (92), the use of tricyclic drugsincreased the risk of MI by a factor of 2.2 (95% CI1.33.9) after adjustment for numerous confound-ers. In the same study, SSRI use was not associated
with any change in risk of MI. A larger casecontrol study comparing 60 000 cases of MI and360 000 matched controls (93) found that bothtricyclics (OR 1.90, 95% CI 1.153.14) and SSRIs(OR 2.59, 95% CI 1.444.66) were associated withan increased risk of MI.
These findings in relation to SSRIs are in somecontrast to those of other studies. For example,Sauer et al. (94) analysed a total of 653 cases offirst MI compared with 2990 control subjects insmokers aged 3065 years. The risk of first MI wassubstantially reduced in current SSRI users (OR
0.35, 95% CI 0.180.68) but unaltered in a smallergroup of subjects receiving non-SSRI antidepres-sants. Adjustment was made for 15 confoundingvariables by multivariate logistic regression.
The same research team used a similar method inanalysing a larger cohort (1080 cases of first MI,4256 controls) of subjects aged 4075 (95).
Adjusted OR for first MI among users of paroxe-tine, fluoxetine and sertraline was 0.59 (95% CI0.390.91). Moreover, affinity of individual SSRIdrugs for the serotonin transporter was signifi-cantly (negatively) correlated with the risk of MI,suggesting that this is the mechanism affordingprotection against MI [SSRIs reduce plateletaggregation by inhibiting platelet storage of sero-tonin; (96)]. One further study (97) using patientdata from the UK General Practice researchdatabase compared 3319 patients with first MIwith 13 139 matched controls. Neither previous
nor current use of any group of antidepressantswas associated with altered risk of MI.
Discussion
This literature review uncovered a wealth of dataexamining the interactions between depression,antidepressants and cardiovascular disorders.Depression seems to be an independent riskfactor for the development of coronary diseaseand for cardiac death after MI and stroke. Onepossible mechanism is increased platelet reactivity.The use of certain antidepressants (tricyclics) may
be associated with an increased risk of MI whereasthe use of others (SSRIs) may decrease the risk ofMI. Recent studies have shown that the use ofSSRIs and mirtazapine is safe post-MI and mayeven reduce mortality, although response to treat-ment may be a prerequisite for this beneficial effect.Certain antidepressants (citalopram and paroxe-tine) appear to be safe in coronary artery diseasewhereas others (mainly SSRIs) may improve mor-tality following stroke. The use of antidepressantsis complicated by their various cardiovasculareffects, although SSRIs, mirtazapine, reboxetine
and moclobemide have few important cardiovas-cular adverse effects.In patients at high risk of developing cardiovas-
cular disease (e.g. those with diabetes, hyperten-sion, dyslipidaemia or who smoke or who areoverweight) the use of tricyclic antidepressantsshould be avoided. SSRIs are antidepressants ofchoice in this patient group. Reboxetine, duloxe-tine and venlafaxine should not be used in thosewith hypertension. In patients with establishedcoronary artery disease, specific evidence supportsthe use of citalopram and paroxetine but other
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SSRIs may be presumed to be safe. After MI,sertraline is the drug of choice but, again, otherSSRIs and mirtazapine may confer similar benefits.SSRIs are also antidepressants of first choice inheart failure, in those at risk of arrhythmia andafter stroke. Tricyclics, venlafaxine and trazodoneshould be avoided in patients at risk of arrhythmia.
There is an urgent need for large, controlled,prospective studies examining the effect of differentantidepressants on physical outcomes and mortalityin cardiovascular disease and after MI and stroke.
Declarations of interest
The author has received research funding, consultancy fees and
honoraria from Wyeth, Servier, Lundbeck, Pfizer and Eli Lilly.
References
1. Musselman DL, Evans DL, Nemeroff CB. The relationship of
depressionto cardiovascular disease: epidemiology, biology,and treatment. Arch Gen Psychiatry 1998;55:580592.
2. Cleophas TJ. Depression and myocardial infarction:
implications for medical prognosis and options for treat-
ment. Neth J Med 1998;52:8289.
3. OBrien P, Oyebode F. Psychotropic medication and the
heart. Adv Psychiatr Treat 2003;9:414423.
4. Coupland N, Wilson S, Nutt D. Antidepressant drugs and
the cardiovascular system: a comparison of tricyclics and
selective serotonin reuptake inhibitors and their relevance
for the treatment of psychiatric patients with cardiovas-
cular problems. J Psychopharmacol 1997;11:8392.
5. Vieweg WV, Wood MA. Tricyclic antidepressants, QT
interval prolongation, and torsade de pointes. Psychoso-
matics 2004;45:371377.
6. Jacobs DR Jr, Adachi H, Mulder I et al. Cigarette smokingand mortality risk: twenty-five-year follow-up of the Seven
Countries Study. Arch Intern Med 1999;159:733740.
7. Franco OH, de Laet C, Peeters A, Jonker J, Mackenbach J,
Nusselder W. Effects of physical activity on life expectancy
with cardiovascular disease. Arch Intern Med 2005;165:
23552360.
8. Isomaa B, Almgren P, Tuomi T et al. Cardiovascular
morbidity and mortality associated with the metabolic
syndrome. Diabetes Care 2001;24:683689.
9. Wulsin LR, Singal BM. Do depressive symptoms increase
the risk for the onset of coronary disease? A systematic
quantitative review. Psychosom Med 2003;65:201210.
10. Barth J, Schumacher M, Herrmann-Lingen C. Depressionas a
risk factor for mortality in patients with coronary heart dis-
ease: a meta-analysis. Psychosom Med 2004; 66:802813.11. Nicholson A, Kuper H, Hemingway H. Depression as an
aetiologic and prognostic factor in coronary heart disease:
a meta-analysis of 6362 events among 146 538 participants
in 54 observational studies. Eur Heart J 2006;27:2763
2774.
12. Wulsin LR. Is depression a major risk factor for coronary
disease? A systematic review of the epidemiologic evidence.
Harv Rev Psychiatry 2004;12:7993.
13. Carney RM, Freedland KE, Miller GE, Jaffe AS. Depres-
sion as a risk factor for cardiac mortality and morbidity: a
review of potential mechanisms. J Psychosom Res 2002;
53:897902.
14. Musselman DL, Tomer A, Manatunga AK et al. Exaggerated
platelet reactivity in major depression. Am J Psychiatry
1996;153:13131317.
15. Laghrissi-Thode F, Wagner WR, Pollock BG, Johnson PC,
Finkel MS. Elevated platelet factor 4 and beta-thrombo-
globulin plasma levels in depressed patients with ischemic
heart disease. Biol Psychiatry 1997;42:290295.
16. Yeragani VK, Pohl R, Balon R et al. Heart rate variability
in patients with major depression. Psychiatry Res 1991;
37:3546.
17. Frasure-Smith N, Lesperance F, Talajic M. Depression fol-
lowing myocardial infarction. Impact on 6-month survival.
JAMA 1993;270:18191825.
18. Frasure-Smith N, Lesperance F, Talajic M. Depression and
18-month prognosis after myocardial infarction. Circula-
tion 1995;91:9991005.
19. van Melle JP, de Jonge P, Spijkerman TA et al. Prognostic
association of depression following myocardial infarction
with mortality and cardiovascular events: a meta-analysis.
Psychosom Med 2004;66:814822.
20. Beck AT, Beamesderfer A. Assessment of depression: the
depression inventory. Mod Probl Pharmacopsychiatry
1974;7:151169.
21. Bush DE, Ziegelstein RC, Tayback M et al. Even minimalsymptoms of depression increase mortality risk after acute
myocardial infarction. Am J Cardiol 2001;88:337341.
22. Carney RM, Blumenthal JA, Stein PK et al. Depression,
heart rate variability, and acute myocardial infarction.
Circulation 2001;104:20242028.
23. Kleiger RE, Miller JP, Bigger JT Jr, Moss AJ. Decreased
heart rate variability and its association with increased
mortality after acute myocardial infarction. Am J Cardiol
1987;59:256262.
24. Lesperance F, Frasure-Smith N, Juneau M, Theroux P.
Depression and 1-year prognosis in unstable angina. Arch
Intern Med 2000;160:13541360.
25. Shapiro PA, Lesperance F, Frasure-Smith N et al. An open-
label preliminary trial of sertraline for treatment of major
depression after acute myocardial infarction (the SAD-HAT Trial). Sertraline Anti-Depressant Heart Attack
Trial. Am Heart J 1999;137:11001106.
26. Serebruany VL, Glassman AH, Malinin AI et al. Plate-
let endothelial biomarkers in depressed patients treated
with the selective serotonin reuptake inhibitor sertraline
after acute coronary events: the Sertraline AntiDepressant
Heart Attack Randomized Trial (SADHART) Platelet
Substudy. Circulation 2003;108:939944.
27. Glassman AH, OConnor CM, Califf RM et al. Sertraline
treatment of major depression in patients with acute MI or
unstable angina. JAMA 2002;288:701709.
28. Berkman LF, Blumenthal J, Burg M et al. Effects of treating
depression and low perceived social support on clinical
events after myocardial infarction: the Enhancing Recov-
ery in Coronary Heart Disease Patients (ENRICHD)Randomized Trial. JAMA 2003;289:31063116.
29. Taylor CB, Youngblood ME, Catellier D et al. Effects of
antidepressant medication on morbidity and mortality in
depressed patients after myocardial infarction. Arch Gen
Psychiatry 2005;62:792798.
30. van Melle JP, de Jonge P, Honig A et al. Effects of antide-
pressant treatment following myocardial infarction. Br J
Psychiatry 2007;190:460466.
31. de Jonge P, Honig A, van Melle JP et al. Nonresponse to
treatment for depression following myocardial infarction:
association with subsequent cardiac events. Am J Psychi-
atry 2007;164:13711378.
Taylor
440
-
7/28/2019 Antidepresivos y Enfermedad Cardiovascular
8/9
32. Strik JJ, Honig A, Lousberg R et al. Efficacy and safety of
fluoxetine in the treatment of patients with major depres-
sion after first myocardial infarction: findings from a
double-blind, placebo-controlled trial. Psychosom Med
2000;62:783789.
33. Rigotti NA, Thorndike AN, Regan S et al. Bupropion for
smokers hospitalized with acute cardiovascular disease.
Am J Med 2006;119:10801087.
34. Lesperance F, Frasure-Smith N, Koszycki D et al. Effects of
citalopram and interpersonal psychotherapy on depression
in patients with coronary artery disease: the Canadian
Cardiac Randomized Evaluation of Antidepressant and
Psychotherapy Efficacy (CREATE) trial. JAMA 2007;
297:367379.
35. Nelson JC, Kennedy JS, Pollock BG et al. Treatment of
major depression with nortriptyline and paroxetine in pa-
tients with ischemic heart disease. Am J Psychiatry 1999;
156:10241028.
36. Roose SP, Laghrissi-Thode F, Kennedy JS et al. Comparison
of paroxetine and nortriptyline in depressed patients with
ischemic heart disease. JAMA 1998;279:287291.
37. Pollock BG, Laghrissi-Thode F, Wagner WR. Evaluation of
platelet activation in depressed patients with ischemic heart
disease after paroxetine or nortriptyline treatment. J ClinPsychopharmacol 2000;20:137140.
38. Serebruany VL, OConnor CM, Gurbel PA. Effect of selec-
tive serotonin reuptake inhibitors on platelets in patients
with coronary artery disease. Am J Cardiol 2001;87:1398
1400.
39. Yeragani VK, Pesce V, Jayaraman A, Roose S. Major
depression with ischemic heart disease: effects of paroxe-
tine and nortriptyline on long-term heart rate variability
measures. Biol Psychiatry 2002;52:418429.
40. Robinson RG, Bolduc PL, Price TR. Two-year longitudinal
study of poststroke mood disorders: diagnosis and out-
come at one and two years. Stroke 1987;18:837843.
41. Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, Fedoroff
JP, Price TR. The impact of poststroke depression on
recovery in activities of daily living over a 2-year follow-up. Arch Neurol 1990;47:785789.
42. Ramasubbu R, Robinson RG, Flint AJ, Kosier T, Price TR.
Functional impairment associated with acute poststroke
depression: The Stroke Data Bank Study. J Neuropsychi-
atry Clin Neurosci 1998;10:2633.
43. Williams LS, Ghose SS, Swindle RW. Depression and
other mental health diagnoses increase mortality risk
after ischemic stroke. Am J Psychiatry 2004;161:1090
1095.
44. Chen Y, Guo JJ, Zhan S, Patel NC. Treatment effects of
antidepressants in patients with post-stroke depression: a
meta-analysis. Ann Pharmacother 2006;40:21152122.
45. Rasmussen A, Lunde M, Poulsen DL, Sorensen K, Qvitzau S,
Bech P. A double-blind, placebo-controlled study of
sertraline in the prevention of depression in stroke patients.Psychosomatics 2003;44:216221.
46. Narushima K, Kosier JT, Robinson RG. Preventing post-
stroke depression: a 12-week double-blind randomized
treatment trial and 21-month follow-up. J Nerv Ment Dis
2002;190:296303.
47. Robinson RG, Jorge RE, Moser DJ et al. Escitalopram and
problem-solving therapy for prevention of poststroke
depression: a randomized controlled trial. JAMA
2008;299:23912400.
48. Robinson RG, Schultz SK, Castillo C et al. Nortriptyline
versus fluoxetine in the treatment of depression and in
short-term recovery after stroke: a placebo-controlled,
double-blind study. Am J Psychiatry 2000;157:351359.
49. Wiart L, Petit H, Joseph PA, Mazaux JM, Barat M. Fluo-
xetine in early poststroke depression: a double-blind pla-
cebo-controlled study. Stroke 2000;31:18291832.
50. Narushima K, Paradiso S, Moser DJ, Jorge R, Robinson RG.
Effect of antidepressant therapy on executive function after
stroke. Br J Psychiatry 2007;190:260265.
51. Jorge RE, Robinson RG, Arndt S, Starkstein S. Mortality
and poststroke depression: a placebo-controlled trial of
antidepressants. Am J Psychiatry 2003;160:18231829.
52. Glassman AH, Johnson LL, Giardina EG et al. The use of
imipramine in depressed patients with congestive heart
failure. JAMA 1983;250:19972001.
53. Roose SP, Glassman AH, Giardina EG et al. Nortriptyline in
depressed patients with left ventricular impairment. JAMA
1986;256:32533257.
54. Roose SP, Glassman AH, Giardina EG, Johnson LL, Walsh
BT, Bigger JT Jr. Cardiovascular effects of imipramine and
bupropion in depressed patients with congestive heart
failure. J Clin Psychopharmacol 1987;7:247251.
55. Roose SP, Glassman AH, Attia E, Woodring S, Giardina EG,
Bigger JT Jr. Cardiovascular effects of fluoxetine in de-
pressed patients with heart disease. Am J Psychiatry
1998;155:660665.
56. Strik JJ, Honig A, Lousberg R, Cheriex EC, Van Praag HM.Cardiac side-effects of two selective serotonin reuptake
inhibitors in middle-aged and elderly depressed patients.
Int Clin Psychopharmacol 1998;13:263267.
57. Roose SP, Dalack GW, Glassman AH, WoodringS, WalshBT,
Giardina EG. Cardiovascular effects of bupropion in de-
pressed patients with heart disease. Am J Psychiatry 1991;
148:512516.
58. Cheeta S, Schifano F, Oyefeso A, Webb L, Ghodse AH.
Antidepressant-related deaths and antidepressant pre-
scriptions in England and Wales, 1998-2000. Br J Psychi-
atry 2004;184:4147.
59. Henry JA, Antao CA. Suicide and fatal antidepressant
poisoning. Eur J Med 1992;1:343348.
60. Morgan O, Griffiths C, Baker A, Majeed A. Fatal toxicity of
antidepressants in England and Wales, 19932002. HealthStat Q 2004;23:1824.
61. Buckley NA, McManus PR. Fatal toxicity of serotoninergic
and other antidepressant drugs: analysis of United King-
dom mortality data. BMJ 2002;325:13321333.
62. Henry JA, Alexander CA, Sener EK. Relative mortality
from overdose of antidepressants. BMJ 1995;310:221224.
63. Ansel GM, Coyne K, Arnold S, Nelson SD. Mechanisms of
ventricular arrhythmia during amitriptyline toxicity.
J Cardiovasc Pharmacol 1993;22:798803.
64. Cohen H, Hoffman RS, Howland MA. Cyclic antidepressant
poisoning: a review and case report. J Pharm Pract 1993;
6:89102.
65. Thanacoody HK, Thomas SH. Tricyclic antidepressant poi-
soning: cardiovascular toxicity. Toxicol Rev 2005;24:205
214.66. Buckley NA, Dawson AH, Whyte IM, Henry DA. Greater
toxicity in overdose of dothiepin than of other tricyclic
antidepressants. Lancet 1994;343:159162.
67. Reid F, Henry JA. Lofepramine overdosage. Pharmacop-
sychiatry 1990;23(suppl. 1):2327.
68. Habuchi Y, Furukawa T, Tanaka H, Tsujimura Y, Yoshimura
M. Block of Na+ channels by imipramine in guinea-pig
cardiac ventricular cells. J Pharmacol Exp Ther 1991;
256:10721081.
69. Valenzuela C, Sanchez-Chapula J, Delpon E, Elizalde A,
Perez O, Tamargo J. Imipramine blocks rapidly activating
anddelays slowly activatingK+ current activationin guinea
pig ventricular myocytes. Circ Res 1994;74:687699.
Antidepressant drugs and cardiovascular pathology
441
-
7/28/2019 Antidepresivos y Enfermedad Cardiovascular
9/9
70. Nau C, Seaver M, Wang SY, Wang GK. Block of human
heart hH1 sodium channels by amitriptyline. J Pharmacol
Exp Ther 2000;292:10151023.
71. Giardina EG, Bigger JT Jr, Glassman AH, Perel JM, Kantor
SJ. The electrocardiographic and antiarrhythmic effects of
imipramine hydrochloride at therapeutic plasma concen-
trations. Circulation 1979;60:10451052.
72. The Cardiac Arrhythmia Suppression Trial (CAST) Inves-
tigators. Preliminary report: effect of encainide and fle-
cainide on mortality in a randomized trial of arrhythmia
suppression after myocardial infarction. N Engl J Med
1989;321:406412.
73. Roose SP, Glassman AH. Antidepressant choice in the pa-
tient with cardiac disease: lessons from the Cardiac
Arrhythmia Suppression Trial (CAST) studies. J Clin
Psychiatry 1994;55(suppl. A):8387.
74. Khawaja IS, Feinstein RE. Cardiovascular effects of selec-
tive serotonin reuptake inhibitors and other novel antide-
pressants. Heart Dis 2003;5:153160.
75. Gasic S, Korn A, Eichler HG, Oberhummer I, Zapotoczky HG.
Cardiocirculatory effects of moclobemide (Ro 11-1163), a
new reversible, a short-acting MAO-inhibitor with prefer-
ential type A inhibition, in healthy volunteersand depressive
patients. Eur J Clin Pharmacol 1983;25:173177.76. Gamble DE, Peterson LG. Trazodone overdose: four years
of experience from voluntary reports. J Clin Psychiatry
1986;47:544546.
77. Levenson JL. Prolonged QT interval after trazodone over-
dose. Am J Psychiatry 1999;156:969970.
78. de Meester A, Carbutti G, Gabriel L, Jacques JM. Fatal
overdose with trazodone: case report and literature review.
Acta Clin Belg 2001;56:258261.
79. Khalifa M, Daleau P, Turgeon J. Mechanism of sodium
channel block by venlafaxine in guinea pig ventricular
myocytes. J Pharmacol Exp Ther 1999;291:280284.
80. Rudolph RL, Derivan AT. The safety and tolerability of
venlafaxine hydrochloride: analysis of the clinical trials
database. J Clin Psychopharmacol 1996;3(suppl. 2):54S
59S.81. Whyte IM, Dawson AH, Buckley NA. Relative toxicity of
venlafaxine and selective serotonin reuptake inhibitors in
overdose compared to tricyclic antidepressants. QJM
2003;96:369374.
82. Colbridge MG, Volans GN. Venlafaxine in overdose
experience of the National Poisons Information Service
(London centre). J Toxicol Clin Toxicol 1999;37:383.
83. Mines D, Hill D, Yu H, Novelli L. Prevalence of risk factors
for suicide in patients prescribed venlafaxine, fluoxetine,
and citalopram. Pharmacoepidemiol Drug Saf
2005;14:367372.
84. Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews
E. Risk of suicide during treatment with venlafaxine, cit-
alopram, fluoxetine, and dothiepin: retrospective cohort
study. BMJ 2007;334:242.
85. Vieweg WV, Julius DA, Fernandez A et al. Treatment of
depression in patients with coronary heart disease. Am J
Med 2006;119:567573.
86. Denolle T, Pellizzoni C, Jannuzzo MG, Poggesi I. Hemo-
dynamic effects of reboxetine in healthy male volunteers.
Clin Pharmacol Ther 1999;66:282287.
87. Wohlreich MM, Mallinckrodt CH, Prakash A, Watkin JG,
Carter WP. Duloxetine for the treatment of major
depressive disorder: safety and tolerability associated with
dose escalation. Depress Anxiety 2007;24:4152.
88. Thase ME. Effects of venlafaxine on blood pressure: a
meta-analysis of original data from 3744 depressed pa-
tients. J Clin Psychiatry 1998;59:502508.
89. Paton C, Ferrier IN. SSRIs and gastrointestinal bleeding.
BMJ 2005;331:529530.
90. Jakobsen J, Hauksson P, Vestergaard P. Heart rate variation
in patients treated with antidepressants. An index of anti-
cholinergic effects? Psychopharmacology 1984;84:544548.
91. Coull DS, Crooks J, Dingwall-Fordyce K, Scott AM, Weir
RD. A method of monitoring drugs for adverse reactions
II. Amitriptyline and cardiac disease. Eur J Clin Pharma-
col 1970;3:5155.92. Cohen HW, Gibson G, Alderman MH. Excess risk of myo-
cardial infarction in patients treated with antidepressant
medications: association with use of tricyclic agents. Am J
Med 2000;108:28.
93. Tata LJ, West J, Smith C et al. General population based
study of the impact of tricyclic and selective serotonin re-
uptake inhibitor antidepressants on the risk of acute
myocardial infarction. Heart 2005;91:465471.
94. Sauer WH, Berlin JA, Kimmel SE. Selective serotonin re-
uptake inhibitors and myocardial infarction. Circulation
2001;104:18941898.
95. Sauer WH, Berlin JA, Kimmel SE. Effect of antidepressants
andtheirrelative affinityfor theserotonin transporter on the
risk of myocardial infarction. Circulation 2003;108:3236.
96. von Kanel R. Platelet hyperactivity in clinical depressionand the beneficial effect of antidepressant drug treatment:
how strong is the evidence? Acta Psychiatr Scand
2004;110:163177.
97. Meier CR, Schlienger RG, Jick H. Use of selective serotonin
reuptake inhibitors and risk of developing first-time acute
myocardial infarction. Br J Clin Pharmacol 2001;52:179
184.
98. Guy W (ed.). The Clinical Global Impressions Scale. In:
ECDEU Assessment Manual for Psychopharmacology,
revised edition. Rockville, MD: National Institute of
Mental Health, 1976:157169.
99. Hamilton M. A rating scale for depression. J Neurol Neu-
rosurg Psychiatry 1960;23:5662.
Taylor
442