Can Chantix (varenicline) worsen anxiety and depression in patients with a history of mental health issues?

Can Chantix Worsen Anxiety and Depression?

Based on the highest quality evidence from the landmark EAGLES trial and FDA labeling, Chantix (varenicline) does NOT significantly worsen anxiety or depression compared to placebo, even in patients with pre-existing psychiatric disorders, though postmarketing reports have documented rare cases requiring immediate discontinuation. 1, 2

Evidence from the EAGLES Trial (2016)

The most definitive evidence comes from the large EAGLES randomized controlled trial, which specifically evaluated neuropsychiatric safety in two cohorts:

Non-Psychiatric Cohort (N=3,912):

• Varenicline was NOT associated with increased incidence of clinically significant neuropsychiatric adverse events (composite endpoint including anxiety, depression, hostility, agitation, aggression, delusions, hallucinations, homicidal ideation, mania, panic, and irritability) 1
• Serious neuropsychiatric events occurred in only 0.1% of varenicline-treated patients versus 0.4% of placebo-treated patients 1

Psychiatric Cohort (N=4,003 with diagnosed psychiatric disorders):

• More events were reported overall compared to the non-psychiatric cohort, but the risk difference versus placebo was modest: 2.7% (95% CI: -0.05 to 5.4) for varenicline 1
• This was comparable to bupropion at 2.2% and nicotine patch at 0.4% 1
• Serious neuropsychiatric events occurred in 0.6% of varenicline-treated patients (0.5% requiring psychiatric hospitalization) versus 0.6% of placebo-treated patients (0.2% requiring hospitalization) 1
• Importantly, varenicline was associated with significantly higher abstinence rates than other treatments, demonstrating superior efficacy 1

FDA Labeling and Postmarketing Surveillance

Despite the reassuring trial data, the FDA label includes important warnings based on postmarketing reports:

Documented Neuropsychiatric Events:

• Postmarketing reports have included changes in mood (depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide 2
• These events occurred in patients both with and without pre-existing psychiatric disease 2
• Some patients experienced worsening of their pre-existing psychiatric illnesses 2

Critical Distinction:

• Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood 2
• Depression, rarely including suicidal ideation, has been reported in smokers undergoing cessation attempts WITHOUT medication 2
• However, some adverse events occurred in patients taking varenicline who CONTINUED to smoke, suggesting the medication itself may contribute 2

Clinical Management Algorithm

Pre-Treatment Assessment:

• Obtain psychiatric history and assess for current mood disorders, anxiety, or suicidal ideation 1
• Conduct suicide risk assessment before prescribing 1
• Current morbidity or distress may suggest postponement of varenicline and use of cessation counseling with NRT instead 1

Monitoring During Treatment:

• Observe patients closely for neuropsychiatric adverse events, particularly agitation, depressed mood, changes in behavior or thinking, suicidal ideation, or suicidal behavior 2
• Advise patients and caregivers to report these symptoms immediately 2

If Neuropsychiatric Symptoms Emerge:

• Stop varenicline immediately and contact healthcare provider 1, 2
• Evaluate severity of symptoms and extent of treatment benefit 2
• Consider options: dose reduction, continued treatment under closer monitoring, or discontinuation 2
• Provide ongoing monitoring and supportive care until symptoms resolve (symptoms may persist in some cases even after discontinuation) 2

Reconciling Conflicting Evidence

Why the discrepancy between trial data and postmarketing reports?

The EAGLES trial provides the highest quality evidence showing no significant increase in neuropsychiatric events with varenicline versus placebo 1. However, several factors explain the postmarketing reports:

• Nicotine withdrawal itself causes anxiety, depression, and mood changes, making causality difficult to establish 1, 2
• Research in brain-damaged patients who quit smoking without medication showed NO increased depression, suggesting varenicline-associated psychiatric complications are medication-related rather than cessation-related 3
• Postmarketing surveillance captures rare events that may not appear in controlled trials 2
• Individual susceptibility varies, and some patients may experience idiosyncratic reactions 4

Special Populations

Patients with Psychiatric History:

• Multiple studies show varenicline can be used effectively in patients with stable psychiatric conditions 5, 6
• One study found no difference in abstinence rates between patients with and without psychiatric history (31.5% vs 35.4% at 6 months) 5
• Side effects were rated as moderate intensity or less, with minimal differences between psychiatric and non-psychiatric groups 5, 6
• However, patients with psychiatric history reported slightly more neuropsychiatric symptoms (tension/agitation, irritability, confusion, depression, anxiety) though intensity was similar 6

Patients with Depression:

• One trial showed varenicline increased smoking cessation rates WITHOUT exacerbating anxiety and depression symptoms in adults with stably treated current or past depression 1
• Depression and stress scores declined in both depressed and non-depressed groups taking varenicline 6

Common Pitfalls to Avoid

1. Do not dismiss patient concerns about mood changes - While trial data is reassuring, individual patients may experience genuine medication-related psychiatric effects requiring immediate discontinuation 2

2. Do not attribute all mood symptoms to nicotine withdrawal - Research suggests varenicline itself can cause psychiatric complications in some patients 3

3. Do not continue varenicline if neuropsychiatric symptoms emerge - The FDA label explicitly recommends immediate discontinuation and evaluation 2

4. Do not prescribe without proper psychiatric screening - Assess suicide risk and current psychiatric status before initiating treatment 1

Risk-Benefit Consideration

The substantial benefits of smoking cessation must be weighed against the risks of neuropsychiatric adverse events 1. The NCCN guidelines note that serious side effects are extremely rare, and the panel considers varenicline to have a favorable risk/benefit ratio for use in patients with cancer who smoke 1. The European guidelines similarly concluded that the slightly increased risk of cardiovascular and psychiatric events does not outweigh the benefits of smoking cessation 1.

Bottom line: Varenicline can be used safely in most patients, including those with psychiatric history, but requires careful monitoring and immediate discontinuation if mood changes, anxiety, depression, or suicidal ideation develop.