In a recently released Public Health Advisory, the U.S. Food and Drug Administration (FDA) issued a second alert to the public about severe psychiatric side-effects linked to the smoking-cessation drug, Chantix.
Back in November 2006 when the FDA published its initial findings, they were only able to state a potential-but still unclear-link between the use of Chantix and severe alterations in mood and behavior. Now, "potential" has moved up to an "increasingly likely association." In post-market reports, the FDA received claims of 37 suicides and over 400 incidences of suicidal behavior relating to the use of Chantix.
Pfizer, the manufacturer of Chantix, agreed to update the warning and precautions section in its prescribing information for doctors, caregivers and patients. Pfizer now includes in its warning information that "Serious neuropsychiatric symptoms have occurred in patients being treated with Chantix..." and that "All patients being treated with Chantix should be observed for neuropsychiatric symptoms including changes in behavior, agitation, depressed mood, suicidal ideation and suicidal behavior. These symptoms, as well as worsening of pre-existing psychiatric illness, have been reported..."
Pfizer also emphasized in the same warning section that no direct link has been established between its product and these side-effects; and, further, that mood changes may be a symptom of nicotine withdrawal alone.
One area in the warnings section stands out: the caution noted specifically for patients with schizophrenia, bipolar disorder, and major depressive disorder, as the safety of Chantix has not been established for persons with these illnesses. The safety has not been established because persons with these illnesses were not included in their studies. That is a choice to exclude millions of people. Call me a skeptic, but I think this exclusion was intentional. For the FDA to not take into account the notable exclusion of persons with psychiatric illness in clinical trials is hard to ignore, particularly for a drug that increases dopamine levels.
Nicotine, Dopamine and Chantix
When nicotine enters the body, it attaches to receptor sites in the brain that then release dopamine. Dopamine (a hormone, neurotransmitter, and neurohormone) is associated with several sensations (pleasure, love, addiction, motivation) and important brain functions (behavior and cognition, motor activity, motivation and reward, sleep, mood, attention, and learning).
The way Chantix works is to block the nicotine from attaching to the receptor sites (thus blocking the sensation of pleasure associated with smoking). Chantix also provides a low dose of dopamine to off-set the withdrawal symptoms (irritability, etc.).
When Pfizer obtained FDA approval for Chantix in May 2006, the FDA knew that the participants in the clinical trials did not include anyone with a psychiatric illness or a psychiatric illness history. I realize there is a push on the FDA to approve medications faster to get them to market. But these post-market psychiatric risk findings should not be surprising. Too much is already known and established about the role of dopamine in psychiatric illness treatment.
The role of dopamine in treating psychiatric illness is well documented. A few examples:
- Antipsychotic medications are dopamine-lowering medications utilized for the treatment of both psychosis and schizophrenia.
- Risperdal (risperidone), a dopamine-reducing drug, is used for both bipolar disorder and major depression treatment.
- MAOI's (Monoamine Oxidase Inhibitors) are classified into two groups: MAO-A and MAO-B. The MAO-B, specifically, works as a dopamine-increasing medication. For both MAO classes, when taken in combination with any other medication that acts on epinephrine, norepinephrine or dopamine, they must be given at very low dosages in order to maintain their antidepressant effects.
- Some SNRI's (Selective Norepinephrine Reuptake Inhibitors) like Effexor can weakly inhibit the reuptake of dopamine. When taken at high dosages, other SNRI's (Cymbalta) can also reuptake dopamine.
- Bupropion's (Wellbutrin) inhibit the reuptake of both norepinephrine and dopamine. (Zyban, another smoking cessation drug, is a bupropion.)
Upon even a mini-review of the role of dopamine in psychiatric medications, it becomes clear that dopamine levels require monitoring-no matter how low the dosage. Too much or too little dopamine is what creates mood and behavioral disturbances. (At this point no studies point to contraindications for benzodiazepines [the main anti-anxieties in use like Xanax, Klonopin, Restoril, and Ativan] and dopamine-only that they both activate the pleasure centers in the brain. The same holds true for SSRI's [Selective Serotonin Reuptake Inhibitors]. In fact, many believe that some SSRI's actually lower the amount of dopamine released. In any case, any increase in dopamine needs to be monitored.)
For the FDA to essentially ignore the basic side-effect profile of dopamine at the outset when approving this drug and not insist upon some type of clear warning or that those with psychiatric illnesses were at greater risk (and also not studied), I feel they did the mental health community at large a grave disservice. In light of the expanding knowledge of "dual-diagnosis (abuse/addiction co-occurring with mental illness) we would be a population to consider when highlighting the risk factors for a smoking-cessation drug.
On the other hand, for a pharmaceutical company to acknowledge and intensify its warning information (even with the added emphasis that no direct link has been established) continues to clear the way for increased public attention to mental health in general as well as illness. Even a seemingly benign smoking-cessation drug can severely affect mood and behavior.
Although it took less than a year on the market for the truth to come out, this has been almost a year of unnecessary grief for far too many people who thought they were making an informed choice.
 "Public Health Advisory-Important Information on Chantix (varenicline)" February 1, 2008, U.S. Food and Drug Administration
 "FDA: Chantix may post psychiatric risks" Washington, Associated Press, February 2, 2008
 "Chantix-Full Prescribing Information (varenicline) Tablets" Pfizer Labs, Division of Pfizer, Inc. January 2008