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

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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

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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.

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