Thursday January 31 2013
Citalopram is a widely prescribed antidepressant in the UK
"Heart risk link to SSRI antidepressants confirmed," BBC News reports. The BBC goes on to say that "some but not all antidepressant drugs known as SSRIs pose a very small but serious heart risk".
This news, which was reported well by the BBC was based on good quality research into the relationship between the electrical activity of the heart and use of antidepressant medication.
Researchers were particularly interested in potential risks associated with a kind of SSRI antidepressant called citalopram, as it has been the subject of recent warnings by European and US drug regulators. Other SSRI antidepressants were included in the study as well. The researchers were also interested in an older tricyclic antidepressant called amitriptyline, which is also used to treat nerve pain.
The researchers examined the medical records of tens of thousands of patients who had been prescribed an antidepressant and had also had an electrocardiogram (ECG). They found that some of the drugs being studied were associated with a disturbance of the electrical activity of the heart, which increased at higher doses of the medication.
While these changes in the electrical activity of the heart represent a theoretical increase in the risk of serious heart rhythm problems, such events are quite rare. Doctors are already aware that these drugs carry this potential risk. As a result, new recommendations about antidepressant dosage were released in 2011. The news is that there is now more research to support a link between certain antidepressants and heart problems, not that there is a sudden shift in the evidence.
Where did the story come from?
The study was carried out by researchers from Massachusetts General Hospital and Brigham and Women’s Hospital in the US and was funded by the US National Institutes of Health and National Library of Medicine.
The study was published as an open access article in the peer-reviewed British Medical Journal.
The BBC covered this story appropriately, from the headline through to discussion of the risks versus the benefits of antidepressant use. The Daily Telegraph similarly reported on the balance of risks and benefits. However, its headline: “the most widely-used antidepressant in Britain increases the risk of potentially fatal heart rhythm problems”, is not strictly correct.
The researchers were not looking at heart rhythm problems – only at changes to the heart’s electrical activity, which could potentially lead to heart rhythm problems.
What kind of research was this?
This was a cross-sectional study that examined the association between doses of antidepressant medication and a variation in the electrical activity of the heart, as measured by an electrocardiogram (ECG).
An ECG measures the electrical activity of the heart as it beats. The electrical activity of one heartbeat is traced on the ECG in five segments. These are called the P, Q, R, S and T segments. These segments indicate how the electrical signals flow through the chambers of the heart. The change in electrical activity that this study was interested in was the duration between the Q wave and the T wave – known as the QT interval.
When the QT interval is prolonged, this means that electrical activity is spreading through the heart slightly slower, and this may carry a risk of triggering a rare condition of abnormal electrical activity known as torsade de pointes.
The main risk of torsade de pointes is that this may lead to a serious condition known as ventricular tachycardia, which is a very rapid heart rate that carries the risk of progressing to cardiac arrest (where the heart stops pumping blood around the body).
This study examined the link between antidepressant medication use and prolonged QT interval – the first step in a chain of risk factors. It is important to note that it did not directly assess the link between taking an antidepressant and having or developing a serious heart rhythm problem.
The US Food and Drug Administration (FDA) has previously warned about the use of high doses of citalopram, which is a commonly prescribed SSRI antidepressant medication, because of concerns over its association with prolonged QT intervals.
This prompted the UK’s regulatory body, the Medicines and Healthcare products Regulatory Agency (MHRA) to amend its dosage guidance so that it no longer recommends high doses of SSRIs.
As this was a cross-sectional study, we cannot say for certain whether the medication directly caused the change in electrical activity seen. The presence of a dose-response relationship (where the QT interval is more prolonged at higher medication doses) supports the theory that the medication caused the changes seen. However, other criteria must be met, and this research must be supported with more robust evidence, before we can be absolutely certain of the nature of the relationship.
What did the research involve?
The researchers accessed the health records of patients who had been prescribed antidepressant medications (including SSRIs and tricyclics), and who underwent an ECG test to trace the heart’s electrical signal after they were prescribed the medication.
The researchers classified each patient according to which drug they were prescribed. They analysed the association between each drug and the length of the QT interval using a variety of statistical models. There are standard categories of QT interval duration associated with higher risk of future heart rhythm problems. The researchers classified the patients into these categories based on their ECG results.
In this analysis, they took into account several variables that may confound the relationship between medication use and QT interval, including:
- history of major depression
- history of cardiovascular disease
What were the basic results?
The study included 38,397 patients. Of these, about a quarter were prescribed the SSRI citalopram. Approximately 20% of the study participants were classified as having an abnormal or high QT interval, and this percentage did not vary greatly between the medications.
The researchers found that increasingly large doses of several antidepressants were significantly associated with increased QT interval. These antidepressants included the SSRIs citalopram and escitalopram, and the tricyclic antidepressant amitriptyline.
The drug bupropion (used to treat nicotine dependence and to help people quit smoking) was found to be significantly associated with decreasing QT interval at higher doses.
The other medications examined had no significant association with QT interval.
How did the researchers interpret the results?
The researchers conclude that there is a modest increase in the QT interval among patients treated with some antidepressants, but that the sizes of these associations were small, and the clinical implication of this increase is not known.
This study shows a link between three antidepressants (two SSRIs and one tricyclic) and prolonged QT interval (a risk factor for rare but serious heart rhythm problems). The study did not assess the risk of these heart rhythm problems directly (which is difficult to measure because of their rarity). The researchers point out that the recent FDA warning over the risks of citalopram was based on its association with prolonged QT interval only, and “in spite of the epidemiological data showing no difference in risk for arrhythmia [heart rhythm abnormality]”.
The researchers say that certain SSRIs were not significantly associated with risk of prolonged QT interval, and that these medications may be preferable treatment options for people with other cardiac risk factors.
Although this evidence backs up previous evidence in this area, the study has several limitations that should be considered. First, there is a risk that the manner in which patients were selected for the study may bias its results. This is because the researchers did not include all patients who were prescribed an antidepressant, but only those who underwent an ECG as well. As ECGs are not routinely conducted for patients treated with antidepressants, this may automatically have excluded patients at lower risk of having a prolonged QT interval, biasing the results towards those patients with prolonged QT intervals.
The authors examined the differences between the participants included in the study (those with an antidepressant prescription and an ECG) and those excluded because they hadn’t had an ECG. When they did this they found that the research group tended to be older, with more comorbidities (illnesses in addition to that being treated with antidepressants), and that they used more healthcare services than the “excluded” group of patients.
Therefore, the associations found in this study should not be assumed to apply to all people taking antidepressants. The authors report that their results are most relevant to older, sicker patients being treated with antidepressants, and not to an “average” (presumably meaning a younger and otherwise healthy) patient.
A second limitation worth noting is that – as the authors point out – the study did not assess a hard clinical outcome, such as torsade de pointes, but rather chose the “proxy outcome” of QT interval. Prolonged QT interval will not necessarily develop into a serious heart rhythm problem. And this study cannot tell us whether individuals taking citalopram, escitalopram and amitriptyline are at increased risk of these problems.
A third limitation to consider (again pointed out by the researchers) is that the patients were not randomly assigned to treatment, and this may confound the results. This is because doctors may make treatment decisions on factors not included in the present analysis.
Overall, this study suggests that some patients being treated with antidepressants may be at increased risk of prolonged QT interval. It isn’t possible to say whether this risk translates into increased risk of serious heart problems, nor is it possible to estimate the size of this risk.
This research provides valuable further information on the association of certain antidepressants with prolonged QT interval – a risk factor already recognised by the medical profession. However, further research is needed to examine any link between antidepressant use and heart rhythm problems.
In conclusion, the results of this study probably won’t affect most people using antidepressants. The potential risk that a prolonged QT interval will cause a serious complication is small and the benefits of antidepressant treatment outweigh the risk in many cases. However, this reinforces that all such risks need to be considered by patients and their doctors when medication is chosen or reviewed.
If you are concerned about the medication you have been prescribed never stop taking it without first speaking to the doctor who is responsible for your treatment and care.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.