Neuropsychiatric Adverse Events Associated With Varenicline
Neuropsychiatric Adverse Events Associated With Varenicline
Figure 1 summarises the selection of studies. The search strategy identified 1089 studies from the computerised databases (476 from Medline, 517 from PsycINFO, and 96 from Embase). One additional trial was identified from CENTRAL and clinical.trials.gov. Out of the 1090 studies, 130 were duplicates and 905 were excluded based on screening of titles and abstracts; therefore 55 papers met the criteria for further screening. After the second round of screening, 42 trials were identified for further data extraction. Two additional studies were identified when the search was repeated for the week beginning Monday 4 August 2014. Forty four studies were included in the systematic review. We received responses from study authors for 33 studies (75%).
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Figure 1.
Flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline.
Table 1 and Appendix 2 describe study characteristics. The trials included 11,146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo). Of these randomised patients, 10,998 were evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group). The duration of treatment ranged from one week to 52 weeks, while study duration ranged from eight days to 53 weeks. Eighteen trials (61.3% of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses ( Table 2 ). In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 26.6 years in the varenicline group and 20 cigarettes a day for 26.2 years in the placebo group. Loss to follow-up ranged from 0% to 60% in both groups ( Appendix 2 ). In 12 trials losses to follow-up were higher in the varenicline group than the placebo group, whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group.
Table 3 shows the assessment of risk of bias. We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains or because no data were reported in the published papers and the study authors did not respond to our requests for data. This resulted in exclusion of 114 patients (1.9%) from the varenicline group and 123 patients (2.4%) from the placebo group; 10,761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group). In three trials there were high losses to follow-up, 53.7%, 60%, and 45.2%, respectively. These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded. They were all small trials (combined total of n=92 in the varenicline group (1.6% of all people randomised to varenicline in our meta-analysis) and n=86 in the placebo group (1.7% of all people randomised to placebo)). In addition, only nine out of 178 patients (5.1%) were lost to follow-up because of adverse events, and these were mostly gastrointestinal in nature (such as nausea and vomiting).
Two people died by suicide (both in the varenicline arms) and four attempted to do so (two in the varenicline arm and two in the placebo arm). Table 4 summarises the Peto odds ratios, risk differences, and 95% confidence interval for the primary and secondary outcomes. Because of the small numbers of events, we combined suicide and attempted suicide into a single outcome. Thirty one trials reported suicide and suicide attempt; the Peto odds ratio for varenicline versus placebo was 1.67 (95% confidence interval 0.33 to 8.57; P=0.54, I=10.3%) and the risk difference was 0.0003 (−0.002 to 0.003; P=0.81, I=0.0%). Twenty trials reported suicidal ideation (Figures 2 and 3); the Peto odds ratio was 0.58 (0.28 to 1.20; P=0.14, I=0.0%) and the risk difference was −0.003 (−0.009 to 0.002; P=0.24, I=0.0%). Thirty one trials reported on depression (Figures 4 and 5); the Peto odds ratio was 0.96 (0.75 to 1.22; P=0.74, I=0.0%) and the risk difference was −0.001 (−0.01 to 0.01; P=0.74, I=0.0%). Death was reported in 36 trials (total 13/5760 in the varenicline group and 11/4887 in the placebo group). The Peto odds ratio for death was 1.05 (0.47 to 2.38; P=0.9, I=38.7%), and there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 0.0001, −0.003 to 0.003; P=0.94, I=0.0%) ( Table 4 ). The forest plots for the secondary outcomes are shown in Appendix 3.
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Figure 2.
Forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials.
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Figure 3.
Risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool.
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Figure 4.
Summary of Peto odds ratios, risk differences, and 95% confidence intervals for neuropsychiatric events in people treated with varenicline.
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Figure 5.
Comparison of Peto, fixed effects, and random effects odds ratios (OR) for insomnia, sleep disorders, and abnormal dreams in people treated with varenicline.
We found no evidence of an increased risk of irritability (odds ratio 0.98, 05% confidence interval 0.81 to 1.17; P=0.79, I=0.0%), aggression (0.91, 0.52 to 1.59; P=0.75, I=20.8%), or somnolence (1.23, 0.94 to 1.62; P=0.13, I=10.4%) as the confidence intervals included the null value of 1. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07; P<0.001, I=0.0%), insomnia (1.56, 1.36 to 1.78; P<0.001, I=0.0%), abnormal dreams (2.38, 2.05 to 2.77; P<0.001, I=22.3%), and fatigue (1.28, 1.06 to 1.55; P=0.01, I=6.3%), with some evidence of a reduced risk of anxiety (0.75, 0.61 to 0.93; P=0.008, I=5.7%). Consistent findings were observed for the risk differences ( Table 4 ).
There were minimal differences in the effect measures and 95% confidence intervals with Peto, fixed effects, and random effects odds ratios ( Table 5 ).
The subgroup analyses are shown in Appendix 4 for the primary outcomes of depression and suicidal ideation. Subgroup tests showed no evidence of a variation in the side effects of depression and suicidal ideation by age group (P=0.391 and P=0.933, respectively, for interaction), percentage of men in the study (P=0.418 and P=0.925), percentage of white people in the study (P=0.685 and P=0.254), presence or absence of psychiatric illness (P=0.126 and P=0.304), smoking status (P=0.906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers), and whether the trial was industry sponsored or not (P=0.386 and P=0.380). The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses compared with those where none of the participants had psychiatric illness were 1.49 (95% confidence interval 0.84 to 2.65) versus 0.91 (0.69 to 1.21) for depression and 0.79 (0.32 to 1.93) versus 0.34 (0.09 to 1.29) for suicidal ideation.
The funnel plots for depression and insomnia are shown in Appendix 5. The P values for funnel plot asymmetry were 0.53 for depression and 0.93 for insomnia (that is, there was no evidence against the null hypothesis of no small study effects).
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Appendix 5. Funnel plots [posted as supplied by author].
Figure 1. Depression.
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Appendix 5. Funnel plots [posted as supplied by author].
Figure 2. Insomnia.
Results
Study Characteristics
Figure 1 summarises the selection of studies. The search strategy identified 1089 studies from the computerised databases (476 from Medline, 517 from PsycINFO, and 96 from Embase). One additional trial was identified from CENTRAL and clinical.trials.gov. Out of the 1090 studies, 130 were duplicates and 905 were excluded based on screening of titles and abstracts; therefore 55 papers met the criteria for further screening. After the second round of screening, 42 trials were identified for further data extraction. Two additional studies were identified when the search was repeated for the week beginning Monday 4 August 2014. Forty four studies were included in the systematic review. We received responses from study authors for 33 studies (75%).
(Enlarge Image)
Figure 1.
Flow chart showing selection of randomised controlled trials for inclusion in systematic review of varenicline.
Table 1 and Appendix 2 describe study characteristics. The trials included 11,146 participants (6015 patients were randomised to receive a maximum of varenicline 1 mg twice daily and 5131 patients received a placebo). Of these randomised patients, 10,998 were evaluable for adverse events (5931 in the varenicline group and 5067 in the placebo group). The duration of treatment ranged from one week to 52 weeks, while study duration ranged from eight days to 53 weeks. Eighteen trials (61.3% of all participants) included cigarette smokers from the general population with no history of psychiatric illnesses ( Table 2 ). In trials that included cigarette smokers (39 trials) participants smoked an average of 20 cigarettes a day for 26.6 years in the varenicline group and 20 cigarettes a day for 26.2 years in the placebo group. Loss to follow-up ranged from 0% to 60% in both groups ( Appendix 2 ). In 12 trials losses to follow-up were higher in the varenicline group than the placebo group, whereas in 17 trials losses to follow-up were higher in the placebo group than the varenicline group.
Table 3 shows the assessment of risk of bias. We excluded five trials from the meta-analysis as the risk of bias was unclear in four or more of the six domains or because no data were reported in the published papers and the study authors did not respond to our requests for data. This resulted in exclusion of 114 patients (1.9%) from the varenicline group and 123 patients (2.4%) from the placebo group; 10,761 patients were included in the meta-analyses (5817 in the varenicline group and 4944 in the placebo group). In three trials there were high losses to follow-up, 53.7%, 60%, and 45.2%, respectively. These studies were assessed as low risk of bias because of incomplete outcome data and were not excluded. They were all small trials (combined total of n=92 in the varenicline group (1.6% of all people randomised to varenicline in our meta-analysis) and n=86 in the placebo group (1.7% of all people randomised to placebo)). In addition, only nine out of 178 patients (5.1%) were lost to follow-up because of adverse events, and these were mostly gastrointestinal in nature (such as nausea and vomiting).
Risk of Neuropsychiatric Adverse Events and Death
Two people died by suicide (both in the varenicline arms) and four attempted to do so (two in the varenicline arm and two in the placebo arm). Table 4 summarises the Peto odds ratios, risk differences, and 95% confidence interval for the primary and secondary outcomes. Because of the small numbers of events, we combined suicide and attempted suicide into a single outcome. Thirty one trials reported suicide and suicide attempt; the Peto odds ratio for varenicline versus placebo was 1.67 (95% confidence interval 0.33 to 8.57; P=0.54, I=10.3%) and the risk difference was 0.0003 (−0.002 to 0.003; P=0.81, I=0.0%). Twenty trials reported suicidal ideation (Figures 2 and 3); the Peto odds ratio was 0.58 (0.28 to 1.20; P=0.14, I=0.0%) and the risk difference was −0.003 (−0.009 to 0.002; P=0.24, I=0.0%). Thirty one trials reported on depression (Figures 4 and 5); the Peto odds ratio was 0.96 (0.75 to 1.22; P=0.74, I=0.0%) and the risk difference was −0.001 (−0.01 to 0.01; P=0.74, I=0.0%). Death was reported in 36 trials (total 13/5760 in the varenicline group and 11/4887 in the placebo group). The Peto odds ratio for death was 1.05 (0.47 to 2.38; P=0.9, I=38.7%), and there was no evidence of an increased risk of death in the varenicline group compared with the placebo group (risk difference 0.0001, −0.003 to 0.003; P=0.94, I=0.0%) ( Table 4 ). The forest plots for the secondary outcomes are shown in Appendix 3.
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Figure 2.
Forest plot of risk of suicidal ideation events (Peto odds ratio) associated with varenicline use in 20 placebo controlled randomised trials.
(Enlarge Image)
Figure 3.
Risk of bias assessment for each trial of varenicline using Cochrane risk of assessment of bias tool.
(Enlarge Image)
Figure 4.
Summary of Peto odds ratios, risk differences, and 95% confidence intervals for neuropsychiatric events in people treated with varenicline.
(Enlarge Image)
Figure 5.
Comparison of Peto, fixed effects, and random effects odds ratios (OR) for insomnia, sleep disorders, and abnormal dreams in people treated with varenicline.
We found no evidence of an increased risk of irritability (odds ratio 0.98, 05% confidence interval 0.81 to 1.17; P=0.79, I=0.0%), aggression (0.91, 0.52 to 1.59; P=0.75, I=20.8%), or somnolence (1.23, 0.94 to 1.62; P=0.13, I=10.4%) as the confidence intervals included the null value of 1. Varenicline was associated with an increased risk of sleep disorders (1.63, 1.29 to 2.07; P<0.001, I=0.0%), insomnia (1.56, 1.36 to 1.78; P<0.001, I=0.0%), abnormal dreams (2.38, 2.05 to 2.77; P<0.001, I=22.3%), and fatigue (1.28, 1.06 to 1.55; P=0.01, I=6.3%), with some evidence of a reduced risk of anxiety (0.75, 0.61 to 0.93; P=0.008, I=5.7%). Consistent findings were observed for the risk differences ( Table 4 ).
Sensitivity Analyses
There were minimal differences in the effect measures and 95% confidence intervals with Peto, fixed effects, and random effects odds ratios ( Table 5 ).
Subgroup Analyses
The subgroup analyses are shown in Appendix 4 for the primary outcomes of depression and suicidal ideation. Subgroup tests showed no evidence of a variation in the side effects of depression and suicidal ideation by age group (P=0.391 and P=0.933, respectively, for interaction), percentage of men in the study (P=0.418 and P=0.925), percentage of white people in the study (P=0.685 and P=0.254), presence or absence of psychiatric illness (P=0.126 and P=0.304), smoking status (P=0.906 for depression but not calculated for suicidal ideation as there were no reports of suicidal ideation in studies that included non-smokers), and whether the trial was industry sponsored or not (P=0.386 and P=0.380). The effect estimates (odds ratio) for the trials in which all participants had psychiatric illnesses compared with those where none of the participants had psychiatric illness were 1.49 (95% confidence interval 0.84 to 2.65) versus 0.91 (0.69 to 1.21) for depression and 0.79 (0.32 to 1.93) versus 0.34 (0.09 to 1.29) for suicidal ideation.
Small Study Effects
The funnel plots for depression and insomnia are shown in Appendix 5. The P values for funnel plot asymmetry were 0.53 for depression and 0.93 for insomnia (that is, there was no evidence against the null hypothesis of no small study effects).
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Appendix 5. Funnel plots [posted as supplied by author].
Figure 1. Depression.
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Appendix 5. Funnel plots [posted as supplied by author].
Figure 2. Insomnia.
