Varenicline and the risk of neuropsychiatric adverse events and death

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Smoking is the leading cause of preventable morbidity and premature death in the UK and internationally (Peto et al., 2000) and costs the National Health Service around £5 billion annually, therefore smoking cessation aids are important for those wishing to quit.

The most clinically effective drug for short term abstinence in smoking cessation is Varenicline (Cahill et al., 2013), which was licensed in the UK in 2006. Concerns about the drug’s neuropsychiatric safety led to issued warnings from the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2008 (MHRA, 2008) and in 2009 the United States Food and Drug Administration (FDA) has required the black box warning (the strongest safety warning) to the labelling of varenicline (FDA, 2009).

A recent meta-analysis (Gibbons & Mann, 2013) found no evidence of an increased risk of depression, suicide or non-fatal self-harm (see Fluharty, 2014). However, a criticism raised was that this study was sponsored by industry and there is evidence that industry sponsored trials may report outcomes favourable to the study sponsor (Etter et al., 2007).

To provide a comprehensive evaluation Thomas and colleagues (2015) conducted a systematic review and meta-analysis to determine the risk of neuropsychiatric adverse events and death in all published randomised placebo controlled trials of varenicline.

Concerns about the neuropsychiatric safety of varenicline have led to MHRA (2008) and FDA (2009) warnings.

Methods

Authors sought randomised placebo controlled trials of any duration of varenicline at the maximum dose (1mg twice daily) in smokers and non-smokers.

Primary outcome measures were neuropsychiatric adverse events including:

  • Suicide
  • Attempted suicide
  • Suicidal ideation
  • Depression

Secondary outcomes included other neuropsychiatric outcomes (abnormal dreams, aggression, anxiety, fatigue, insomnia, irritability, sleep disorders, somnolence) and death.

Results

The meta-analysis included 39 studies, totalling 10,761 patients, with 5,817 patients prescribed a dose of 1mg of varenicline twice daily and 5,844 prescribed placebo. The duration of treatment ranged from one week to 52 weeks.

Primary outcomes

  • Two people died by suicide (both in varenicline arms) and four attempted to do so (two in the varenicline arms and two in the placebo)
  • There was no evidence of an increased risk of:
    • Suicide or suicide attempt (OR = 1.67, 95% CI = 0.33 to 8.57; p = 0.54)
    • Suicidal ideation (OR = 0.58, 95% CI 0.28 to 1.20; p = 0.14)
    • Depression (OR = 0.96, CI 95% 0.75 to 1.22; p = 0.74)
    • Death (OR = 1.05, CI 95% 0.47 to 2.38; p = 0.9)

Secondary outcomes

  • There was no evidence of an increased risk of:
    • Irritability (OR = 0.98, 95% CI = 0.81 to 1.17; p = 0.79)
    • Aggression (OR = 0.91, 95% CI = 0.52 to 1.59; p = 0.75)
    • Somnolence (OR = 1.23, 95% CI = 0.94 to 1.62; p = 0.13)
  • Varenicline was associated with an increased risk of:
    • Sleep disorders (OR = 01.63, 95% CI = 1.29 to 2.07; p < 0.001)
    • Insomnia (OR = 1.56, 95% CI = 1.36 to 1.78; p < 0.001)
    • Abnormal dreams (OR = 2.38, 95% CI = 2.05 to 2.77; p < 0.001)
    • Fatigue (OR = 1.28, 95% CI = 1.06 to 1.55; p = 0.01)
  • There was some evidence of a reduced risk of:
    • Anxiety (OR = 0.75, 95% CI = 0.61 to 0.93; p = 0.008)
  • There was no evidence of a variation in the side effects of depression and suicidal ideation by age group, gender, ethnic origin, presence or absence of psychiatric illness, smoking status and whether the trial was industry sponsored or not.
The review

The review found that varenicline was associated with an increased risk of sleep disorders, insomnia, abnormal dreams and fatigue.

Discussion

This review finds no increased risk of suicide or attempted suicide, suicidal ideation, depression or death in those treated with varenicline; these results are consistent with a previous meta-analysis (Gibbons & Mann, 2013).

Authors conclude that the health benefits of varenicline for smoking cessation outweigh the risks for suicidal behaviour which they describe as currently unproved. They state:

The reduction in varenicline prescribing in the UK should be as much a cause for concern to clinicians, regulatory agencies, and policy makers as the unfounded fears regarding varenicline’s association with suicidal behaviour.

Limitations

The study has some limitations. The authors emphasise that due to the small number of suicides and attempted suicides (n=6) major adverse effects for this outcome can’t be ruled out.

A recent editorial (Harrison-Woolrych, 2015) describes the reasons for the possible disconnect between the findings of meta-analyses and ‘real life’ evidence from case reports showing associations with the drug and mental health side effects (e.g. Harrison-Woolrych & Ashton, 2011). The strict inclusion and exclusion criteria in randomised controlled trials means history of psychiatric illness is often an exclusion criteria, for example in the current meta-analysis, 61.3% of all participants had no history of psychiatric illness. Therefore those in randomised controlled trials might have a lower risk of psychiatric effects than those stopping smoking in real life.

A third of the studies included in the meta-analysis included a majority of men, and it’s been shown that women are over-represented in the group who experience psychiatric events (Harrison-Woolrych & Ashton, 2011). Other aspects of clinical trials that could explain differences in findings compared to case reports are that they often include the recommended 12 weeks of treatment, whereas in real life treatment periods vary. Furthermore the close monitoring in such trials could reduce the risk for adverse events (Harrison-Woolrych, 2015).

Conclusions

The author’s conclusion that that the concerns around suicide are unfounded should be taken carefully. Given the small number of suicide and attempted suicides (n=6), major adverse events for this outcome cannot be ruled out.

Further research is needed to determine whether different smoking populations (e.g., those with existing psychiatric disorders) are more vulnerable to the potential varenicline-associated risks.

The reviewers urge caution and call for further relevant studies before we draw any hard conclusions about the neuropsychiatric safety of varenicline

The reviewers urge caution and call for further relevant studies before we draw any hard conclusions about the neuropsychiatric safety of varenicline

If you need help

If you need help and support now and you live in the UK or the Republic of Ireland, please call the Samaritans on 116 123.

If you live elsewhere, we recommend finding a local Crisis Centre on the IASP website.

We also highly recommend that you visit the Connecting with People: Staying Safe resource.

Links

Primary study

Thomas, K. H., Martin, R. M., Knipe, D. W., Higgins, J. P. T., & Gunnell, D. (2015). Risk of neuropsychiatric adverse events associated with varenicline: systematic review and meta-analysis. BMJ, 350:h1109 doi: http://dx.doi.org/10.1136/bmj.h1109

Other references

Cahill K, Stevens S, Perera R, Lancaster T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD009329. DOI: 10.1002/14651858.CD009329.pub2.

Etter, J. F., Burri, M., & Stapleton, J. (2007). The impact of pharmaceutical company funding on results of randomized trials of nicotine replacement therapy for smoking cessation: a meta-analysis. Addiction, 102, 815-822. doi: 10.1111/j.1360-0443.2007.01822.x [PubMed abstract]

Fluharty, M. Varenicline, smoking cessation and neuropsychiatric adverse events. The Mental Elf, 17 Feb 2014

Gibbons, R. D., & Mann, J. J. (2013). Varenicline, smoking cessation, and neuropsychiatric adverse events (PDF). Am J Psychiatry, 170, 1460-1467. doi: 10.1176/appi.ajp.2013.12121599

Harrison-Woolrych, M. & Ashton, J. (2011) Psychiatric adverse events associated with varenicline: an intensive postmarketing prospective cohort study in New Zealand. Drug Saf, 34, 763-72 [PubMed abstract]

Harrison-Woolrych, M. (2015). Mental health effects of varenicline. BMJ, 350:h1168.

US Food and Drug Administration (FDA) (2009) black box warning: Information for healthcare professionals: varenicline (marketed as Chantix) and bupropion (marketed as Zyban, Wellbutrin, and generics). Silver Spring, Md, FDA.

Medicines and Healthcare Products Regulatory Agency (MHRA) (2008). Varenicline: adverse psychiatric reactions, including depression. Drug Safety Update, 2, 2–3.

Peto R, Darby S, Deo H, Silcocks P, Whitley E, Doll R. (2000). Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case-control studies. BMJ, 321: 323.

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