Although a history of MD was not associated with severity never of symptoms in the current study and a history of GAD was only weakly associated with symptoms, individuals with these disorders tend to be more nicotine dependent; thus, a history of psychopathology could potentially be indicative of risk. Furthermore, consideration of the current findings could improve phenotype refinement in gene finding efforts since individuals experiencing strong symptoms of negative affect upon smoking cessation might be more likely to harbor genetic variants influencing ND than are individuals who do not experience these symptoms. These analyses should be considered in light of several limitations. The sample is restricted to twins born in Virginia and is primarily Caucasian; the findings might not be applicable to other ethnicities or populations.

In addition, the items addressing affect-related symptoms of withdrawal were limited (see Methods section) and retrospective and are thus susceptible to recall bias. We emphasize that these variables potentially encompass a range of withdrawal constructs that are not necessarily mood related; for example, a respondent might endorse feeling anxious in cases where the symptom could be better described as psychomotor agitation or the anxiety was experienced somatically rather than psychologically. Furthermore, we did not have information on the duration of quit attempts, which could be informative given that the course of withdrawal varies across individuals.

In addition, we did not control for baseline (prequit) measures of negative affect beyond MD and GAD diagnoses, which makes it difficult to interpret our assessment of cessation-induced negative affect; Shiffman, West, and Gilbertand (2004) recommend that multiple prequit assessments be taken to account for baseline instability. Additional research that parallels the current analyses, but more thoroughly characterizes both baseline phenotypes and the withdrawal syndrome in terms of symptoms, duration, etc., is needed to confirm the findings reported herein. We also note that these results might not be generalizable to subclinical anxiety or depression or to internalizing disorders other than MD and GAD, such as panic disorder, dysthymia, etc.; this limitation is particularly relevant given recent findings, suggesting that the relationships between smoking behaviors and anxiety differs across disorders (e.

g., Cougle et al., 2010). Potential differences in the relationships among other types of anxiety disorders, ND, and withdrawal-related symptoms of anxiety or depression should be the topic of future research. Finally, the diagnostic categories of MD and GAD are less statistically powerful than would be a continuous GSK-3 measure and this could have led to false
Tobacco smoking is one of the major public health problems worldwide (World Health Organization Report on the Global Tobacco Epidemic, 2009).