Tricyclic Antidepressants Linked to Increased Cardiovascular Risk

Megan Brooks

November 30, 2010

November 30, 2010 — Findings from a prospective cohort study released today suggest tricyclic antidepressants (TCAs) are associated with a 35% increased risk for cardiovascular disease (CVD), which is not explained by existing psychiatric illness.

However, researchers found no increased cardiac risk associated with selective serotonin reuptake inhibitors (SSRIs).

"This suggests that there may be some characteristic of tricyclics that is raising the risk," Mark Hamer, PhD, of University College London, United Kingdom, said in a release. "Tricyclics are known to have a number of side effects; they are linked to increased blood pressure, weight gain, and diabetes, and these are all risk factor for CVD," he adds.

Dr. Hamer told Medscape Medical News that clinicians need to "be cautious about prescribing TCAs, especially in people with other risk factors."

In the study, published online December 1 in the European Heart Journal, Dr. Hamer and colleagues assessed the association between antidepressant medication use and future risk for CVD in 14,784 Scottish adults with no known history of CVD.

All were participants in the Scottish Health Survey, which collects information from the general population every 3 to 5 years. Data from separate surveys in 1995, 1998, and 2003 were combined and linked with records on hospital admissions and deaths, with follow-up until 2007. Individuals with a history of clinically confirmed CVD were excluded.

According to the investigators, 729 (4.9%) of the 14,784 study subjects reported using antidepressant medication: 2.2% reported TCA use, 2% reported SSRI use, and 0.7% reported taking other antidepressants.

Findings Support Previous Research

During an average of 8 years of follow-up, there were 1434 CVD events, of which 26.2% were fatal. After adjusting for various confounding factors, including indicators of mental illness, there was a 35% increased risk for CVD associated with TCA use (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.03 – 1.77).

There was also a nonsignificant association between TCA use and coronary heart disease events (969 events; multivariate HR, 1.24; 95% CI, 0.87 – 1.75).

In contrast, SSRI use was not associated with increased CVD risk (HR, 1.11; 95% CI, 0.77 – 1.60) and neither class of drug was associated with all-cause mortality.

"Our study is the first to contain a representative sample of the whole community, including elderly and unemployed participants, men and women, [and] our data are largely consistent with the few previous studies in healthy people," Dr. Hamer said.

In 1 such study, use of TCAs was associated with about a 2-fold increased relative risk for myocardial infarction during 4.5 years of follow-up, compared with subjects who did not use antidepressants. There was no increased risk with SSRIs in this study (Cohen et al. Am J Med. 2000).

The absence of information on medication compliance and dosage is a limitation of the current study, Dr. Hamer and colleagues note. However, because this was an observational study, it is not possible to infer causation, they add, and it is "plausible that the results could be explained by residual confounding due to unmeasured or unknown risk factors."

Consider CVD in Depressed Patients

Reached for outside comment, Andrew H. Kemp, PhD, MAPS, of the University of Sydney, Australia, who was not involved in the study, called the findings "interesting and important," and he said the findings are "consistent with the well-known, increased anticholinergic effects of TCAs."

"These effects," Dr. Kemp explained, "are likely to be due to the effects on the heart and involve blockade of the muscarinic acetylcholine receptors at the sinoatrial node of the heart, the generator of the sinus rhythm. Blockade of these receptors leads to inhibition of parasympathetic activity and tachycardia.

"While TCAs are associated with greater affinity to muscarinic receptors, SSRIs are more benign, with the exception of paroxetine, which has considerable antimuscarinic potency," Dr. Kemp continued. "Decreased parasympathetic activity leads to increased heart rate and a decrease in heart rate variability, the latter of which may predict sudden cardiac death, even in relatively healthy individuals without a prior history of CVD."

In a study published in Biological Psychiatry in October 2010, Dr. Kemp and colleagues showed that major depressive disorder without CVD is associated with reductions in heart rate variability and that antidepressants do not reverse the observed reductions. This, they say, highlights the need to consider the cardiovascular system in patients presenting with and being treated for depression (Kemp et al. Biol Psychiatry. 2010).

Dr. Hamer and colleagues and Dr. Kemp have disclosed no relevant financial relationships.

Eur Heart J. Published online December 1, 2010.

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