Varenicline's Reversed Black Box Warning
The FDA removed varenicline's neuropsychiatric black box warning in 2016 after a trial specifically designed to test it in patients with her exact diagnosis — the outdated caution has outlived the evidence behind it.
P.N., a 44-year-old accounts payable clerk, has smoked roughly a pack a day for over twenty years and has tried to quit four times using nicotine patches and gum alone, relapsing within a few weeks each time. She has a history of recurrent major depression, currently in sustained remission on sertraline 100mg for the past three years, with a PHQ-9 of 3 at her last two visits. She has no other chronic illness.
Her primary care physician raised varenicline as the next option, given its superior quit rates compared to nicotine replacement alone in most head-to-head trials, and P.N. immediately recalled hearing years ago that the drug was linked to suicidal thoughts and had a serious warning because of it — a concern that made her hesitant even to consider it, and one her physician, who trained before the warning was reversed, admitted she wasn't entirely current on either.
The warning P.N. is remembering was real: the FDA added a black box warning to varenicline in 2009 based on post-marketing reports of neuropsychiatric adverse events, including suicidal ideation, in patients using it to quit smoking. What has changed since is a large, purpose-built randomized trial — EAGLES, published in 2016 — that specifically enrolled both psychiatric and non-psychiatric cohorts, including patients with depression like her, and compared varenicline against bupropion, nicotine patch, and placebo. It found no significant increase in neuropsychiatric adverse events with varenicline compared to the other options, in either cohort. The FDA removed the black box warning later that same year based on those results. The actual clinical question in front of the team isn't whether the old warning was legitimate when it was issued — it was a reasonable response to real post-marketing signals at the time — but whether continuing to treat it as current is still doing her a disservice now that better evidence exists.
At the smoking-cessation planning visit
The warning she remembers was genuinely appropriate for its time — those early post-marketing reports were a real signal worth investigating seriously, not a false alarm. What's different now is EAGLES, a trial built specifically to answer this question rigorously: over eight thousand participants, psychiatric and non-psychiatric cohorts studied separately, varenicline compared head-to-head against bupropion, nicotine patch, and placebo.
The result was no significant increase in neuropsychiatric adverse events with varenicline in either cohort, including the psychiatric cohort her own history would place her in — which is exactly why the FDA removed the warning in 2016 rather than just softening its language.
I'd add that her current stability is itself a favorable sign independent of the varenicline question — three years of sustained remission on a stable sertraline dose gives us a real baseline to monitor against, and EAGLES specifically included patients with a treated psychiatric history similar to hers, not just psychiatrically healthy volunteers.
Routine mood check-ins during the quit attempt are reasonable given any major behavior change can be stressful, but that's standard practice for any smoking cessation effort, not a varenicline-specific precaution the current evidence still supports.
I'll be honest that I hadn't fully updated my own working knowledge on this, and I'd rather correct that directly with her than let outdated caution quietly steer her away from the option with the best quit-rate evidence. I'm comfortable prescribing varenicline with the standard monitoring we'd do for anyone in a quit attempt, not a special protocol built around a warning that no longer reflects the current evidence.
Varenicline was started on its standard titration schedule alongside her unchanged sertraline, with routine mood check-ins built into her quit-attempt follow-up — the same standard of monitoring appropriate for any patient attempting a major behavior change, not a special protocol reflecting continued distrust of the drug.
P.N.'s physician documented the conversation explicitly, including the EAGLES trial and the 2016 warning removal, both for P.N.'s own reference and as a note to revisit with other patients who may be carrying the same outdated concern forward from years ago.