Over 90% of the reported suicides of people taking anti-smoking drugs over the last 13 years were people taking the drug Chantix (varenicline). And the drug was on the market for only four of those years. Add in other safety concerns about varenicline, and you're left with an extremely poor choice for people who want to quit smoking.

That's the conclusion of a recently published study that looked at reports of adverse events since 1998 for the three major types of smoking cessation drugs: varenicline, the antidepressant bupropion and nicotine replacement products such as gum and patches.

The researchers found 3,249 AERS (adverse event reports) of serious injurious behavior or depression from people taking the three types of smoking cessation drugs from 1998 to 2010. Fully 2,925 of these came from people taking varenicline (90%), compared to 229 for bupropion (7%) and 95 for nicotine replacement products (3%).

Varenicline and bupropion already carry a black box warning to doctors about possible suicide and depression. But there's been little information about how often each drug causes these side effects or comparisons between them of how frequently they do so. This study found that varenicline did so much more frequently than bupropion.

Varenicline has also been linked to aggression and violence in three studies and carries a warning about this. Its effects on vision, cognition and motor control have led to its being banned for airline pilots, air traffic controllers, military pilots and missile crews, and restricted for truck drivers.

Quitting smoking brings undeniable health benefits, but the risks associated with this drug suggest that other methods should be tried first. In the study authors' own words, Chantix or varenicline is "unsuitable for first-line use in smoking cessation."

Often, serious side effects of a drug don't become apparent until years after the drug is first marketed. The place they tend to show up first is the FDA's Adverse Event Reporting System (AERS).

In the current study, the researchers found 3,249 AERS reports of serious injurious behavior or depression from people taking the three types of smoking cessation drugs from 1998-2010. Fully 2,925 of these came from people taking varenicline (90%), compared to 229 for bupropion (7%) and 95 for nicotine replacement products (3%). There were 295 successful suicides; 272 of these were in varenicline users (92%), 19 in bupoprion users (6%) and 4 in nicotine replacement drug users (1%). Results were similar for attempted suicide.

Using a statistical method called disproportionality analysis, the researchers calculated that varenicline was 8.4 times as likely as nicotine replacement products and 2.9 times as likely as bupropion to lead to suicidal behavior or depression.

Disproportionality analysis isn't powerful enough to give a reliable estimate of how frequently a drug causes a particular side effect like suicidal behavior or depression from this small number of cases. But it is an accepted way of measuring whether a drug is causing a higher than normal amount of a particular side effect and of comparing the ability of two different drugs to cause a side effect. Here, it's showing that varenicline seems by far to be the most dangerous of the three anti-smoking treatments.

The researchers speculate that the actual incidence of depression or suicidal behavior from varenicline could be anywhere from around a tenth of a percent to over one percent. It would take information from a much larger number of users to fine tune this estimate.

The study seems to contradict a recent review by the FDA that found no difference in psychiatric hospitalizations between varenicline and nicotine replacement patches. But the study authors explain that this is probably because suicide, depression and other serious psychiatric side effects often don't result in hospitalization.

For people who are taking varenicline, some signs that it's affecting your behavior are thoughts about suicide or dying, new or worse depression, anxiety, panic attacks, feeling very agitated or restless, acting aggressively or being angry or violent. A more complete list can be found in the Chantix Medication Guide.

Suicidal Behavior and Depression in Smoking Cessation Treatments was published by PLoS One on November 2, 2011 and is freely available.