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Acta Psychiatr Scand 2008: 118: 434442 All rights reserved DOI: 10.1111/j.1600-0447.2008.01260.

Copyright 2008 The Author Journal Compilation 2008 Blackwell Munksgaard


ACTA PSYCHIATRICA SCANDINAVICA

Clinical overview

Antidepressant drugs and cardiovascular pathology: a clinical overview of eectiveness and safety
Taylor D. Antidepressant drugs and cardiovascular pathology: a clinical overview of eectiveness and safety. Objective: To review data examining the relationships between depression, antidepressants and cardiovascular disease. Method: Structured searches of PubMed, Medline and Embase conducted in March 2008. Results: Depression and cardiovascular disease are closely associated clinical entities. Depression appears both to cause and worsen cardiovascular disease. Cardiovascular disease is in turn associated with a high incidence of depression. Depression is associated with increased mortality in cardiovascular disease, and after myocardial infarction (MI) and stroke. Many antidepressants have cardiotoxic properties. Tricyclic drugs are highly cardiotoxic in overdose and may induce cardiovascular disease and worsen outcome in established cardiovascular disease. Reboxetine, duloxetine and venlafaxine are known to increase blood pressure. Other antidepressants have neutral or benecial eects in various cardiovascular disorders. Conclusion: Sertraline, uoxetine, citalopram, bupropion and mirtazapine appear to be safe to use after MI; the use of sertraline, and response to citalopram and mirtazapine may improve mortality. Paroxetine and citalopram appear to be safe to use in patients with established coronary artery disease. Limited data suggest that a variety of antidepressants are eective and safe to use after stroke.
Clinical recommendations

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: david.taylor@slam.nhs.uk

Accepted for publication July 18, 2008

All patients diagnosed with depression should be closely monitored for other factors (obesity, hypertension, diabetes, physical inactivity, plasma cholesterol) associated with cardiovascular disease. All patients with depression should be advised to take steps to reduce behaviours (e.g. high alcohol consumption, 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 be fully established. Conclusions are limited by the dearth or absence of data on the use of many antidepressants in cardiovascular disease.

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Antidepressant drugs and cardiovascular pathology


Introduction

Depression and cardiovascular disease are highly prevalent in all societies and so, if only by coincidence, the two will frequently occur together, necessitating careful selection of antidepressant treatment. There is a growing body of evidence suggesting that depression is associated both with the development of coronary artery disease and with increased mortality after myocardial infarction (MI) and stroke (1, 2). Antidepressants show a wide range of cardiovascular eects [arrhythmogenicity, autonomic function changes, reduction in heart variability, hypotension, hypertension and changes in platelet activity (35)] which are highly likely to aect cardiovascular morbidity and mortality. The cardiovascular eects of individual antidepressants vary considerably and selection of the most appropriate drug is of vital importance. Choice of antidepressant is made dicult by the numerous cardiovascular eects of antidepressants and by complex interactions between depression, antidepressant use and cardiovascular mortality.
Aims of the study

To examine the above interactions and make recommendations for safe and eective use of antidepressants in dierent types of cardiovascular disease.
Material and methods

Searches of Pubmed, Medline and Embase were undertaken in March 2008 using the following terms: depression, cardiovascular disease, MI, stroke, antidepressants (as a group and by name), mortality and coronary artery disease. Reference sections of obtained articles were scrutinized for further relevant articles. Where available, published meta-analyses were used in preference to individual studies so as to reduce the complexity of the review.

Results Depression and cardiovascular disease

There is an established association between depression and the development of cardiovascular disease and between depression and cardiovascular mortality. The nature and extent of these associations have yet to be precisely determined, largely because of the failure of many studies to account and adjust for confounding variables such as smoking (6), physical activity (7) and aspects of the metabolic

syndrome (8). An additional limitation to many of these studies is the variety of ways in which depression was diagnosed. Although many describe the occurrence of depression, not all established the diagnosis using widely recognized criteria. In a meta-analysis of 10 studies (9) the relative risk of developing coronary disease in those with a history of depression was estimated to be 1.64 [95% condence interval (CI) 1.411.90]. Four of these studies controlled for only two major confounders and six accounted for three. A metaanalysis of 20 studies examining mortality in subjects with coronary heart disease (10) found that depressive symptoms aorded a substantially increased risk of death [odds ratio (OR), 2.24; 95% CI 1.373.60] after 2 years. After adjustment for other measured risk factors, the relative risk was reduced [hazard ratio (HR), 1.76; 95% CI 1.27 2.43] but still statistically signicant. The ndings of both of these analyses are reected in the largest meta-analysis published to date (54 studies, 146 538 participants) (11). The relative risk of developing coronary heart disease in those with depression was 1.81 (95% CI 1.53 2.15); relative risk of death due to cardiovascular events was 1.80 (1.52.15). Adjustment of the latter estimate for the presence of impaired left ventricular function resulted in a 48% reduction in estimated relative risk. A comprehensive and scholarly review of depression and coronary artery disease (12) evaluated the link between the two entities on seven criteria. It was found that i) there was a good evidence of an association, that ii) depression was a good predictor of coronary artery disease, that iii) there was a fair degree of specicity for depression and coronary artery disease (i.e. depression predicts this better than other physical outcomes), that iv) there was general consistency in study outcome, that v) there was a clear doseresponse eect (the worse the depression, the greater the likelihood of coronary artery disease), that vi) the association was biologically plausible, but that there was vii) insucient evidence to demonstrate that treatment of depression reduced the likelihood of coronary artery disease. These data, taken together, suggest an important association between depression and cardiovascular disease but do not establish causation. Indeed, it is possible and valid to conclude that cardiovascular disease is associated with (and perhaps is a causative factor in) depression. Nonetheless, several mechanisms have been put forward to explain the supposed causative link between depression and cardiovascular disease (13). Perhaps the most 435

Taylor compelling of these is the observation that subjects with depression show exaggerated platelet reactivity (14) which appears to be related to elevated plasma levels of platelet factor 4 and b-thromboglobulin (15). Heart rate variability appears not to be altered in depression (16).
Depression after MI

Around a third of people become depressed in the year after suering an MI (17). Depression worsens outcome after MI. Frasure-Smith et al. followed up 222 patients for 18 months having screened all subjects for depression 515 days post-MI (17, 18). After 6 months (17) adjusted HR for death (taking into account left ventricular dysfunction and previous MI) was 4.29 (95% CI 3.145.44) in those who 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 signicantly associated 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 a large number of confounding factors. Method of assessment of depression had no signicant eect on estimated risk. Many studies dened depression as a score of 10 on the Beck Depression Inventory (20) but there is evidence that scores of 49 are also signicantly associated with increased mortality (21). Depression seems to be linked to reduced heart rate variability in post-MI patients (22), a known risk factor for mortality post-MI (23). Depression may also signicantly increase mortality in people with unstable angina (24).
Antidepressants after MI

Five studies have evaluated the impact of using antidepressants after MI (see Table 1). The Sertraline Anti-Depressant Heart Attack Trial (SADHAT) (2527) examined the use of sertraline in depressed subjects experiencing MI or unstable angina. Initial pilot studies suggested that sertraline was well tolerated (25) and that its use reduced platelet activation in addition to that aorded by co-administered anti-platelet regimens (26). The main study (27) compared 186 subjects given sertraline with 183 given placebo over 24 weeks. The use of sertraline was indistinguishable from placebo on all surrogate measures of cardiovascular safety and did not increase the incidence of cardiovascular events. Sertraline was only marginally more eective than placebo in treating depression an observation, according to the study 436

authors, reecting the brevity and self-limiting nature of a substantial proportion of depression after MI. The Enhancing Recovery in Coronary Heart Disease study (ENRICHD; 28) examined the use of early cognitive behavioural therapy [with additional selective-serotonin reuptake inhibitor (SSRI; usually sertraline) treatment in severely depressed unresponsive subjects] in 1238 subjects compared with 1243 receiving usual care. The study treatment was more eective against depression than usual care but did not eect event-free survival. Antidepressant use (in either subject group) was associated with a signicantly reduced risk of death. A sub-analysis of these antidepressant data (29) suggested that the use of SSRIs was largely responsible for this eect: risk of death or recurrent MI was not altered by the use of non-SSRI antidepressants. In the third and most recent major study (30) [Myocardial Infarction and Depression Intervention Trial, (MIND-IT)], 2177 MI patients were evaluated for depression and randomized to the study intervention (mirtazapine vs. placebo, other antidepressants or no pharmacological treatment) or usual care. The intervention showed no improvement in depression compared with usual care and had no eect on cardiac event rate at 18 months. Sub-analyses of those receiving antidepressants in the intervention arm compared with subjects not receiving antidepressants in the usual care arm showed no eect, protective or otherwise. A follow-up analysis (31) revealed that those responding to mirtazapine or citalopram had a signicantly lower rate of mortality than those prescribed an antidepressant but not responding. These ndings imply that it is response to treatment that is protective against future cardiac events. Two further, smaller studies have suggested that uoxetine (32) and bupropion (33) do not increase cardiovascular risk after MI.
Antidepressants in coronary artery disease

Two prospective studies have addressed the safety and ecacy of antidepressant treatment in coronary artery disease. The Canadian Cardiac Randomized Evaluation of Antidepressant and PsychoTherapy Ecacy (CREATE) trial (34) asse ssed short-term outcome in 284 subjects given citalopram 2040 mg day, placebo, interpersonal therapy (IPT) or standard clinical management. Participants had established coronary artery disease dened as evidence of previous MI, previous cardiac revascularization or angiographic evidence

Antidepressant drugs and cardiovascular pathology


Table 1. Controlled studies of antidepressants in depression after MI Trial Strik et al. (32) Design 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 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 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) and Beck 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 As above but only those 73.9% with depression analysed As above, use of antidepressants in intervention arm and usual care arm included Outcome 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. 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 Conclusions Cardiac changes on fluoxetine deemed clinically insignificant Fluoxetine is safe and effective post-MI

SADHART (27)

Sertraline is safe and effective post-MI unstable angina

ENRICHD (28)

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) (subanalysis of those with depression)

Rigotti et al. (33)

MIND-IT (30)

MIND-IT (sub-analysis by response to treatment)

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 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 As above but sub-analyses of responders to antidepressant treatment (50% reduction in HAM-D or score <9 at 24 weeks). (n = 43) vs. non-responders (n = 27) vs. untreated controls (n = 98) Cardiac safety evaluated by frequency of cardiac events (mortality or re-hospitalization) after 24 weeks of randomization and 18 months after MI

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 nonSSRI antidepressant. Of those on SSRIs 49.5% received sertraline, 28.9% paroxetine, 13.0% flu oxetine, 7.6% citalopram Bupropion did not effect 1 year survival (cardiovascular mortality 0% bupropion, 2% placebo) or cardiovascular events (16% vs. 14%).

SSRIs reduce risk of death in those depressed after MI.

Bupropion safe in smokers post MI.

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

Cardiac event rate 25.6% in non-responders, 11.2% in untreated controls and 7.4% in responders Adjusted HR 2.92 (95% CI 1.087.87)

Non-response to antidepressants persistent depression predicts worse cardiovascular outcome

437

Taylor of at least 50% blockage of one or more coronary artery. Citalopram was more eective against depression than placebo but the eect size was small (0.33). IPT was no better in treating depression than standard clinic care. Citalopram and placebo did not dier with respect to eect on cardiac parameters such as blood pressure, heart rate or ECG change. Of 12 serious cardiovascular events occurring, six occurred in those receiving citalopram and six in those given placebo. In the second study, 81 subjects with coronary artery disease were randomized to paroxetine 20 30 mg day or nortriptyline (plasma level 50 150 ng ml). Both drugs were eective in treating depression (35) but only nortriptyline aected cardiac measures: increased heart rate, reduced heart variability and increased cardiac adverse eects were observed with nortriptyline (36). Paroxetine appears to reduce platelet activation in coronary artery disease (37, 38). Nortriptyline has no eect on platelet activation (37) but reduces heart rate variability (39).
Antidepressants and stroke

sity to cause orthostatic hypotension (5255), an adverse eect observed to be least severe with nortriptyline (53). SSRIs (55, 56) and bupropion (54, 57) (amfebutamone) are not associated with signicant hypotension, ECG changes or changes in left ventricular function in people with heart failure.
Cardiotoxicity of antidepressants

Depression is seen in up to 40% of patients suering stroke (40) and is associated with worsened functional impairment (41, 42) and increased mortality (HR at 3 years: 1.13, 95% CI 1.061.21) (43). A meta-analysis of 16 placebo-controlled studies including 1320 patients (44) concluded that antidepressants were more eective than placebo in treating poststroke depression (response rates 65.18% active treatment; 44.37% placebo). Sertraline, uoxetine, escitalopram and nortriptyline have also been shown to prevent the emergence of depression in stroke patients (4547). The use of antidepressants seems to not aect recovery of cognitive or social functioning (4850), but may reduce risk of death: one study found that 59.2% of patients receiving 12 week poststroke antidepressants were alive 9 years later compared with 36.4% of those receiving placebo (P = 0.03) (51). Data on the eects of antidepressants on mortality poststroke are otherwise limited. In theory, the anti-platelet eect of SSRIs would be expected to decrease the risk of thrombo-embolic stroke and increase the risk of haemorrhagic stroke. The overall eect on mortality is not known but no study has reported an increased risk.
Antidepressants and heart failure

Tricyclic antidepressants are poorly tolerated in people with heart failure because of their propen438

The relative acute cardiotoxicity of antidepressant drugs is suggested by their Fatal Toxicity Index (FTI the number of poisoning deaths per million prescriptions). Estimates of the FTIs for tricyclic antidepressants as a group range from (mean values) 12 (58) to 43 (59, 60), although lofepramine shows uniquely low toxicity [FTI estimated at 1 (58), 1.3 (61) and 2.7 (59)]. Monoamine oxidase inhibitors 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 been estimated at 2 (58, 62) and 4.3 (60), although the FTI for SSRI poisonings involving no other drugs is as low as 1 (60). Trazodone shows moderate toxicity [FTI of around 10 (58, 59, 61)] as does venlafaxine [FTI estimated at 18 (60) and 13 (61, 63)]. Mirtazapine, reboxetine and mianserin have estimated FTIs of a magnitude similar to that of SSRIs (58, 59, 61) although data are relatively limited. There are no data on duloxetine. The FTI data need careful interpretation when considering drug-related cardiotoxicity. In tricyclic overdose, cardiac arrhythmia is probably the most common cause of death (64, 65), although seizures make a signicant contribution with some individual drugs (66). Neither seems to occur with lofepramine (67). Tricyclics are cardiac sodium (INa) and potassium channel (IKr) antagonists (68 70) and prolong QRS and QT intervals, particularly in overdose (65) although small eects are seen in normal doses (71). These quinidine-like eects on sodium channels seem to account for the high incidence of ventricular arrhythmia in overdose (63). Drugs with similar cardiac actions may increase mortality when used in patients at risk of arrhythmia (72) and tricyclics might also be expected to do so (73). Anticholinergic and alphaadrenergic eects of tricyclics cause cardiovascular adverse eects (tachycardia, hypotension) at clinical doses and in overdose. The FTI data for SSRIs, mirtazapine, reboxetine and mianserin imply limited acute toxicity of any sort, so suggesting minimal acute cardiotoxicity. These drugs have no or insignicant eects on the ECG in normal clinical doses (74) and reports of arrhythmia or signicant ECG changes are extre-

Antidepressant drugs and cardiovascular pathology mely rare. Moclobemide, the only monoamine oxidase inhibitor still in widespread use, seems to have no eect on cardiac conduction (75). The FTI of trazodone suggests moderate overdose toxicity. Deaths from overdose with trazodone alone are rare (76) but when death occurs, arrhythmia may be the cause (77, 78). The reported FTI values for venlafaxine are more dicult to interpret. These values suggest moderate acute toxicity and venlafaxine appears to block cardiac sodium channels (79). However, venlafaxine causes no ECG changes in standard doses (80) and only very rarely (i.e. at a frequency similar to that of SSRIs) causes arrhythmia in overdose (81, 82). Its higher FTI may be related to the risk of seizures in overdose (81, 82) or to the possibility that FTI is sometimes a poor measure of toxicity. This is best illustrated by the variation in FTI estimated for individual drugs [estimated FTI for nortriptyline ranges from 1 (60) to 54 (59)]. Other factors are thus clearly important and there is evidence that venlafaxine is prescribed to patients at relatively higher risk of suicide (83, 84).
Other cardiovascular effects

0.35, 95% CI 0.180.68) but unaltered in a smaller group of subjects receiving non-SSRI antidepressants. Adjustment was made for 15 confounding variables by multivariate logistic regression. The same research team used a similar method in analysing a larger cohort (1080 cases of rst MI, 4256 controls) of subjects aged 4075 (95). Adjusted OR for rst MI among users of paroxetine, uoxetine and sertraline was 0.59 (95% CI 0.390.91). Moreover, anity of individual SSRI drugs for the serotonin transporter was signicantly (negatively) correlated with the risk of MI, suggesting that this is the mechanism aording protection against MI [SSRIs reduce platelet aggregation by inhibiting platelet storage of serotonin; (96)]. One further study (97) using patient data from the UK General Practice research database compared 3319 patients with rst MI with 13 139 matched controls. Neither previous nor current use of any group of antidepressants was associated with altered risk of MI.
Discussion

Most tricyclic antidepressants (4) and mirtazapine (85) cause signicant orthostatic hypotension in normal clinical doses. Reboxetine (86), duloxetine (87) and venlafaxine (88) are associated with small increases in blood pressure. SSRIs have important eects on homeostasis and are conclusively linked to an increased risk of bleeding (89).
Antidepressants and risk of MI

Tricyclic antidepressants reduce heart rate variability (90) and have long been suspected of increasing the risk of cardiovascular events, including MI (91). In a US cohort study of members of a health insurance plan (92), the use of tricyclic drugs increased the risk of MI by a factor of 2.2 (95% CI 1.33.9) after adjustment for numerous confounders. In the same study, SSRI use was not associated with any change in risk of MI. A larger case control study comparing 60 000 cases of MI and 360 000 matched controls (93) found that both tricyclics (OR 1.90, 95% CI 1.153.14) and SSRIs (OR 2.59, 95% CI 1.444.66) were associated with an increased risk of MI. These ndings in relation to SSRIs are in some contrast to those of other studies. For example, Sauer et al. (94) analysed a total of 653 cases of rst MI compared with 2990 control subjects in smokers aged 3065 years. The risk of rst MI was substantially reduced in current SSRI users (OR

This literature review uncovered a wealth of data examining the interactions between depression, antidepressants and cardiovascular disorders. Depression seems to be an independent risk factor for the development of coronary disease and for cardiac death after MI and stroke. One possible mechanism is increased platelet reactivity. The use of certain antidepressants (tricyclics) may be associated with an increased risk of MI whereas the use of others (SSRIs) may decrease the risk of MI. Recent studies have shown that the use of SSRIs and mirtazapine is safe post-MI and may even reduce mortality, although response to treatment may be a prerequisite for this benecial eect. Certain antidepressants (citalopram and paroxetine) appear to be safe in coronary artery disease whereas others (mainly SSRIs) may improve mortality following stroke. The use of antidepressants is complicated by their various cardiovascular eects, although SSRIs, mirtazapine, reboxetine and moclobemide have few important cardiovascular adverse eects. In patients at high risk of developing cardiovascular disease (e.g. those with diabetes, hypertension, dyslipidaemia or who smoke or who are overweight) the use of tricyclic antidepressants should be avoided. SSRIs are antidepressants of choice in this patient group. Reboxetine, duloxetine and venlafaxine should not be used in those with hypertension. In patients with established coronary artery disease, specic evidence supports the use of citalopram and paroxetine but other 439

Taylor SSRIs may be presumed to be safe. After MI, sertraline is the drug of choice but, again, other SSRIs and mirtazapine may confer similar benets. SSRIs are also antidepressants of rst choice in heart failure, in those at risk of arrhythmia and after stroke. Tricyclics, venlafaxine and trazodone should be avoided in patients at risk of arrhythmia. There is an urgent need for large, controlled, prospective studies examining the eect of dierent antidepressants on physical outcomes and mortality in cardiovascular disease and after MI and stroke.
Declarations of interest
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