Older tricyclic antidepressants are associated with a 35% increase in the risk of cardiovascular disease (CVD) in adults without a known history of CVD, a cohort study of nearly 15,000 people in Scotland has found.

But use of the newer selective serotonin re-uptake inhibitor (SSRI) antidepressants was not associated with any increased risk of CVD, the study published in the European Heart Journal showed. No significant link was seen between either class of antidepressant and the risk of all-cause mortality. There was a non-significant association between tricyclic antidepressant (TCA) use and coronary heart disease events.

The study by researchers from University College London, the Medical Research Council Social and Public Health Sciences Unit in Glasgow, the University of Edinburgh and Vrije Universiteit Medical Center in the Netherlands was a prospective cohort study of 14,784 initially healthy adults aged 52.4 ± 11.9 years, drawn from Scottish Health Surveys in 1995, 1998 and 2003.

Of these participants, 4.9% reported antidepressant use. The survey data were linked to records of hospital admissions and mortality.

Uncertain evidence

Noting the need to assess the health risks associated with rising antidepressant use across Europe and the US, the authors say recent indications that antidepressants may lead to an increased risk of CVD have been based on uncertain evidence.

“Data from case-control studies, for instance, have produced conflicting results for the two main classes of antidepressant medication [TCAs and SSRIs],” they comment. “Similarly, in prospective studies of participants with existing CVD, the data are also discordant, with some studies suggesting a reduced risk of recurrent myocardial infarction in people taking SSRIs relative to non-users, whereas other studies have shown increased risk in TCA and SSRI users.”

Moreover, the researchers observe, most previous studies have sampled men and
women with existing CVD at entry. Prospective studies of healthy participants “provide a higher level of evidence in this context as it is possible to address the issue of reverse causality which besets case-control studies – i.e., the concern that the mental health consequences of a CVD diagnosis may be generating an increased use of antidepressant medication rather than the converse”, they add.

“Our study is the first to contain a representative sample of the whole community, including elderly and unemployed participants, men and women, etc.,” said lead author Dr Mark Hamer, senior research fellow in the Department of Epidemiology and Public Health at University College London.

“Therefore, our results can be generalised better to the wider community,” he continued. “Given that antidepressants, such as SSRIs, are now prescribed not only for depression, but for a wide range of conditions such as back pain, headache, anxiety and sleeping problems, the risks associated with antidepressants have increasing relevance to the general population.”

Confounding factors

The 35% increase in the risk of CVD seen with TCAs was after accounting for potential confounding factors – which, notably, included symptoms of depression and anxiety. Depression and psychological distress are risk factors for CVD and some previous evidence has suggested the association between antidepressant use and CVD risk is explained by depressive symptoms rather than being a direct effect of pharmacological intervention, the researchers point out.

“On the basis of our findings, the association between antidepressant use and CVD risk is partly independent of psychiatric symptoms, which suggests that there may be some characteristic of TCA that is raising CVD risk,” they comment. “Equally, it is plausible that an elevated rate of CVD of 35% could be explained by residual confounding due to unmeasured or unknown risk factors.”

As Hamer noted, tricyclic antidepressants are linked to increased blood pressure, weight gain and diabetes, all of which are risk factors for cardiovascular disease. At the same time, people taking antidepressants in general are more likely to smoke, be overweight and to do little or no physical activity.

Giving up smoking, losing weight and becoming more active can reduce the risk of CVD two- to three-fold, “which largely outweighs the risks of taking the medications in the first place”, Hamer said. “In addition, physical exercise and weight loss can improve symptoms of depression and anxiety.”

The cohort study findings “suggest that clinicians should be cautious about prescribing antidepressants and should also consider lifestyle advice, such as smoking cessation, exercise and sensible alcohol intake”, he concluded.