Serum nicotine and COT concentrations in smokers with BPD did not differ from those in control smokers without mental illness. This was in contrast to smokers with SCZ, who had higher levels of nicotine from the same number of cigarettes smoked per day. Interestingly, a history of psychosis did not predict greater nicotine intake in smokers with BPD in the present study. Taking an antipsychotic medication similarly did not predict greater nicotine intake, and a high number of BPD subjects reported taking antipsychotic medication.
Seventy to eighty percent of systemically absorbed nicotine is metabolized in the liver by the enzyme CYP2A6 to COT, which is further metabolized into 3-HC by CYP2A6 (43
). The 3-HC:COT ratio is a noninvasive marker of CYP2A6 metabolic activity and is highly correlated with the rate of nicotine metabolism (38
). The NMR (3-HC:COT) in the present study was significantly higher in BPD patients, although this effect was not present when we controlled for those taking hepatic enzyme-inducing antimanic medications. While it is possible that excluding these subjects reduced the statistical power of our tests, we believe that it is more likely that hepatic enzyme-inducing mood-stabilizer medications were responsible for the higher nicotine metabolite ratio in smokers with BPD. Given the trend for higher NMR ratios in individuals taking topirimate, we suspect that this agent increases nicotine metabolism, although we cannot confirm it in this small sample.
People with variants in the CYP2A6
gene that controls the rate of nicotine metabolism differ in their smoking behavior and their propensity toward nicotine dependence. On average, slow metabolizers smoke fewer cigarettes per day, for fewer years, and are more likely to quit in their lifetime compared to fast metabolizers (44
). Fast metabolizers experience more craving in a smoking cessation attempt and are less likely to stop smoking compared to slow metabolizers using the same treatments (49
). Fast metabolizers may experience a lowered therapeutic response to traditional doses of nicotine replacement medications. It is not known if these same effects are seen when rapid metabolism is due to metabolic interactions and not genetic predisposition, although this warrants further study.
Our data corroborated other findings (41
) that African American smokers metabolize nicotine slower than Caucasian smokers. Our data may have been impacted by the low prevalence of African Americans with BPD in the present study. Race is an important characteristic to consider in future studies, as others have found that African Americans are over-diagnosed with SCZ and under-diagnosed with BPD (53
).CYP2A6 activity is also important in the activation of toxic and procarcinogenic compounds found in tobacco smoke (54
). We found significantly higher total puff volume in smokers with BPD. Total puff volume per cigarette is a function of puff number and volume per puff, and is a good index of the ‘work’ that the smoker performs in smoking the cigarette (57
). Estimates of total smoke exposure are essential to understanding differential toxic chemical exposures that result from smoking (58
Smokers with rapid metabolism of nicotine would be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood, and presumably brain. This behavior is consistent with our finding of a shorter IPI in BPD smokers. Prior work in this area, including our own, has shown that shorter IPI is associated with increases in nicotine intake (18
), suggesting that this effect is not unique to mental illness but is a mechanism associated with an intensity of cigarette smoking. Other studies of topography have found an association between the 3-HC:COT ratio and greater total puff volume, suggesting more intense puffing in fast metabolizers, although via a different puffing mechanism (60
). This may also contribute to greater difficulty in quitting smoking. The findings of this study support an increased rate of nicotine metabolism in smokers with BPD taking carbamazepine, oxcarbazepine, and topiramate. As these medications are commonly used for a range of psychiatric and nonpsychiatric conditions, further studies should explore their potential effects on smoking behavior and ability to quit smoking.