Varenicline Suicide Risk
Varenicline does not increase the risk of suicide, suicidal ideation, or other serious neuropsychiatric adverse events compared to placebo or other smoking cessation treatments, even in patients with psychiatric disorders. 1
Evidence from the Landmark EAGLES Trial
The most definitive evidence comes from the large EAGLES trial, which specifically examined neuropsychiatric safety in two cohorts:
- Psychiatric cohort (n=4,116): Patients with diagnosed psychiatric disorders showed no significant increase in neuropsychiatric events with varenicline compared to nicotine patch or placebo 1
- Non-psychiatric cohort (n=4,028): Similarly showed no increased risk 1
The FDA label confirms these findings, noting that in the psychiatric cohort, serious neuropsychiatric events occurred in 0.6% of varenicline-treated patients versus 0.6% of placebo-treated patients 2
Systematic Review Evidence
A 2015 systematic review and meta-analysis of 39 randomized controlled trials identified no evidence that varenicline increases risk of suicide or suicide attempts, suicidal ideation, depression, or death 1. Additionally, a reanalysis of 17 placebo-controlled trials (N=8,027) found varenicline did not increase rates of suicidal events, depression, or aggression/agitation 3.
Real-World Safety Data
A large retrospective review of 164,766 individuals receiving smoking cessation pharmacotherapy found that varenicline posed no elevated risk of neuropsychiatric events (depression, self-harm) compared to nicotine replacement therapy 1.
Clinical Monitoring Recommendations
Despite the reassuring safety data, the FDA label and NCCN guidelines recommend specific monitoring:
- Observe all patients for neuropsychiatric symptoms including agitation, depressed mood, changes in behavior, suicidal ideation, or suicidal behavior 2
- Instruct patients to stop varenicline immediately if they develop agitation, depressed mood, behavioral changes, or suicidal thoughts 2
- Provide closer monitoring in patients with pre-existing psychiatric illness, though the evidence shows no increased risk in this population 1
Important Caveat About Postmarketing Reports
While postmarketing surveillance has documented cases of suicidal ideation and completed suicide in patients taking varenicline, these cases typically occurred in patients with pre-existing psychiatric illness and/or precipitating factors 4. The controlled trial data consistently shows no causal relationship 1, 3, 5.
Risk-Benefit Analysis
The NCCN considers varenicline to have a favorable risk/benefit ratio, noting that the substantial benefits of smoking cessation outweigh the theoretical neuropsychiatric risks 1. Varenicline increases smoking cessation rates by nearly 3-fold compared to placebo and is superior to bupropion and single-form nicotine replacement therapy 6.
Specific Contraindications
The only absolute psychiatric contraindication is in patients with brain metastases who have elevated seizure risk, as seizures (though rare) have been reported with varenicline 1, 2.
Management Algorithm
- Screen for seizure history - avoid varenicline if present, especially with brain metastases 1, 7
- Educate patient and caregivers about neuropsychiatric symptoms to monitor 2
- Initiate standard dosing regardless of psychiatric history 1
- Monitor at each visit for mood changes, behavioral changes, suicidal thoughts 2
- If symptoms emerge: evaluate severity, consider dose reduction or discontinuation, provide ongoing monitoring until symptoms resolve 2
The evidence strongly supports that varenicline can be safely used in patients with psychiatric disorders, including those with past depression or anxiety, with appropriate monitoring 1, 8.