660 patients were prescribed a new course of a smoking cessation product over the study period: the first treatment prescribed was a nicotine replacement product (n=63
265), bupropion (n=6422), or varenicline (n=10
973). Total exposure time was 24
055.6 person years: 18
879.2 person years for nicotine replacement therapies (mean 15.5 weeks per person); 1690.8 person years for bupropion (mean 13.7 weeks per person), and 3485.6 person years for varenicline (mean 16.5 weeks per person).
The characteristics of patients prescribed varenicline were similar to those prescribed bupropion (table 1). Compared with patients prescribed nicotine replacement products, patients prescribed bupropion and varenicline were more often male and less likely to have a history of psychiatric consultation, alcohol misuse, use of psychotropic medication, or self harm or suicidal thoughts. People prescribed bupropion were younger than those prescribed the other products, but the differences were slight. Altogether, 9.5% of patients prescribed varenicline had previously harmed themselves or experienced suicidal thoughts. Almost half of all patients had previously been prescribed a smoking cessation product.
Table 1 Comparison of baseline characteristics of people prescribed different smoking cessation therapies. Values are numbers (percentages) of patients unless stated otherwise
Self harm and suicidal thoughts
Over the follow-up period there were 166 episodes of non-fatal self harm (154 (93%) being cases of self poisoning), two suicides (both in patients prescribed nicotine replacement products, one by means of hanging, the other with a firearm), and 37 episodes of suicidal thoughts. The incidence of self harm, standardised for age and sex, was 533.1 (95% confidence interval 277.0 to 789.2) per 100
000 person years in patients prescribed varenicline, 498.7 (169.1 to 828.2) for bupropion, and 751.7 (627.4 to 876.0) for nicotine replacement products.
The age and sex adjusted hazard ratio for self harm associated with prescribed varenicline was similar to that for bupropion, and the hazard ratios suggest a lower risk of self harm than that associated with nicotine replacement products, although the confidence intervals were wide and included 1.00 (table 2). After controlling for possible confounding factors, we found very weak evidence of an increased risk in relation to both varenicline (hazard ratio 1.12 (0.67 to 1.88)) and bupropion (hazard ratio 1.17 (0.59 to 2.32)). The confounding factors that most strongly contributed to the change in direction of the association with varenicline were past and current use of antidepressants. There was no statistical evidence that associations of smoking cessation products with self harm differed by sex (P(interaction)=0.74), age (P(interaction)=0.70), the timing of the prescribing (before or after media publicity around January 2008) (P(interaction)=0.32), or past psychiatric problems (P(interaction)=0.96).
Table 2 Relative risks of fatal and non-fatal self harm, suicidal thoughts, and depression in people prescribed different smoking cessation products*
In fully adjusted models varenicline was associated with a 43% (95% confidence interval −47% to 285%) increased risk of suicidal thoughts compared with nicotine replacement products. However, the wide confidence intervals were consistent with a large protective effect, no effect, or a large adverse effect.
Of the 64
296 patients not taking antidepressants at baseline, 2244 (3.5%) were treated for depression over the follow-up period. Among these patients there was no evidence in either age and sex adjusted or fully adjusted models that varenicline was associated with an increased risk of developing treated depression compared with nicotine replacement products, and major increases in risk can be ruled out (hazard ratio 0.88 (0.77 to 1.00), table 2).
Sensitivity analyses and all-cause mortality
The risk of self harm and depression with varenicline and bupropion compared with nicotine replacement products were essentially unchanged in (a) models restricted to people who took only one smoking cessation product after 1 September 2006, with adjusted hazard ratios for self harm in relation to varenicline 1.12 (95% confidence interval 0.67 to 1.88) and in relation to bupropion 1.29 (0.63 to 2.66); and (b) models censoring follow-up to 10 weeks after treatment started for all subjects (adjusted hazard ratios for self harm in relation to varenicline 0.93 (0.49 to 1.76) and bupropion (1.10 (0.50 to 2.38)).
Overall 208 participants died over the follow-up period. In age and sex adjusted models we found no evidence that either varenicline or bupropion were associated with an increased risk of all cause mortality risk compared with nicotine replacement therapy (hazard ratios 0.26 (0.13 to 0.53) and 0.56 (0.26 to 1.19) respectively).