Do smoking cessation treatments increase the risk of depression and suicide?

Smoking is a major preventable cause of morbidity and premature mortality throughout the world. There are an estimated 460,000 hospital admissions attributable to smoking in people aged over 35 every year, with an average annual cost to the NHS of £2.7 billion.

Many strategies exist to help people give up smoking. The most common are pharmacological treatments such as nicotine replacement therapy (NRT), bupropion and varenicline. These treatments are recommended by the National Institute of Clinical Excellence (NICE) and have been shown to be effective in increasing smoking cessation (as discussed in previous elf blogs here and here).

However, there have some been concerns that these drugs could have severe side effects including an increased risk of depression, self-harm and suicide. The pharmacological actions of varenicline, a partial nicotinic agonist, may lead to increased impulsivity and aggression. Also, as some smokers report that they smoke in order to self-medicate depression, it is possible that smoking cessation may actually increase depression and the risk of suicide. As a result, both the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) have issued safety warnings for bupropion and varenicline.

A recent study published in the British Medical Journal (Thomas, 2013) set out to compare the risk of depression, self-harm and suicide in patients prescribed varenicline and bupropion. Individuals who were prescribed NRT were used as a comparison group.

Methods

The authors searched the UK’s Clinical Practice Research Datalink (CPRD), a large primary care database in which data from consultations is recorded. This data is linked to mortality data from the Office for National Statistics and Hospital Episode Statistics in the UK. They identified all patients who were aged over 18 years of age, and who had been prescribed a smoking cessation product (varenicline, bupropion or NRT) for the first time from 1^st September 2006 until 31^st October 2011.

They compiled records for 119,546 men and women, 81,545 (68.2%) of whom were prescribed NRT, 31 260 (26.2%) prescribed varenicline and 6 741 (5.6%) prescribed bupropion. The primary outcome measures were incident episodes of depression (measured by the date an antidepressant treatment was administered), and fatal and non-fatal self harm. They also included undetermined deaths, as these are most likely to be suicides. Follow-ups began on the date of first prescription of smoking cessation product and ended with the earliest primary outcome measure. The incidence of risk was measured per person years.

To date, use of the Clinical Practice Research Datalink has resulted in 890 clinical reviews and papers

Results

Throughout the whole sample, there were 92 cases of non-fatal self harm and suicide and 1,094 records of treated depression.

Comparisons of treatments using hazard ratios demonstrated lower risk of treated depression for both varenicline (HR = 0.75, 95% CI, 0.65 to 0.87) and bupropion (HR = 0.63, 95% CI, 0.46 to 0.87), compared with NRT.

There was no evidence for increased risk of fatal or non-fatal self harm when prescribed varenicline (HR = 0.88, 95% CI, 0.42 to 1.49) or bupropion (HR = 0.83, 95% CI, 0.30 to 2.31), compared with NRT.

Importantly, the authors adjusted their models to control for a variety of demographic factors as well as potentially confounding factors, such as year of first prescription and previous use of a smoking cessation product.

The results of this study suggest that there is no evidence of increased risk of suicide, non-fatal self harm or depression in individuals prescribed the smoking cessation medications varenicline or bupropion, compared with NRT

This study suggest that there is no evidence of increased risk of suicide, non-fatal self harm or depression in people prescribed varenicline or bupropion, compared with NRT

Discussion

The results of this study suggest that there is no evidence of increased risk of suicide, non-fatal self harm or depression in individuals prescribed the smoking cessation medications varenicline or bupropion, compared with NRT. The authors therefore suggest that:

These findings should provide some reassurance for users and prescribers of smoking cessation products.

This research has various strengths. The CPRD database is one of the largest in the world and is representative of the UK population as a whole, and the authors repeated their analysis using different strategies to assess possible confounders. These findings also support recent evidence (expertly summarised here by fellow elf Meg Fluharty) suggesting that varenicline does not pose an increased risk of suicidal thoughts or behaviour during or after its use. However, it is noted that the majority of the research synthesised was conducted by Pfizer who market the drug!

But whilst these findings make a significant contribution, some criticisms have been published, and these suggest that the results should be treated with caution. Firstly, the confidence intervals for suicidal behaviour were wide, suggesting we should not completely rule out a link based on this study alone. Secondly, the authors defined depression as being prescribed an antidepressant; however this does not exclude serious depressive symptoms or dysphoric mood that were not treated in this way. Finally, the methodology does not rule out other psychiatric effects such as insomnia or even psychosis (the original authors attempted to respond to these criticisms here).

We can conclude that the results of one study should not influence the warnings supplied with smoking cessation products, and that further studies are needed in order to gain a fuller picture of possible psychiatric side-effects of these medications. Even if such subsequent research reveals that these side-effects are real, this must be balanced against the clear effectiveness of these medications for smoking cessation and the health benefits that follow when people quit smoking.

Some health professionals are calling for more convincing evidence before they completely rule out the possible link between smoking cessation treatments and mental illness