Similarly, co-twin’s neuroticism was largely not associated with severity of withdrawal-induced depressive or anxious symptoms nor was there a significant interaction especially between this term and zygosity. Critical to our analyses, co-twin’s FTND score consistently predicted both outcomes; furthermore, when the interaction between co-twin’s FTND and zygosity was included as a predictor, this term and the main effect of co-twin’s FTND significantly predicted outcome, with monozygotic co-twin’s FTND score more strongly predicting outcome than dizygotic co-twin’s FTND score. The results of these analyses strongly suggest that the severity of nicotine withdrawal-induced depressive and anxious symptoms is a pharmacological component of the nicotine withdrawal syndrome, which is indexed by ND.

Furthermore, this association appears to be driven primarily by genetic influences on liability to ND and withdrawal, with environmental factors playing a less pronounced role: the main effect of co-twin’s FTND score, which is strongly predictive of outcome in nearly every case, is sharply reduced when the co-twin’s FTND �� zygosity interaction term is included in the model (Equations 2, 4, 7, and 8). Parameter estimates from these regressions further suggest that ND is slightly more predictive of withdrawal-induced anxious symptoms than depressive symptoms. The main effects of co-twin’s MD and GAD are not significantly associated with outcome in any regression. Co-twin’s mean neuroticism score, which is positively and significantly correlated with both GAD and MD, is associated with withdrawal-induced depressive symptoms, but not with anxious symptoms.

Nor was the interaction between zygosity and MD, GAD, or mean N associated with either outcome (Equations 1, 3, 5, and 7, respectively). However, results from the within-individual regressions differ slightly in that a history of GAD was associated with withdrawal-induced anxious symptoms, and mean N was associated with both outcomes. The results of within-individual regressions are largely consistent with previous studies that have reported that an individual’s history of anxiety or depression is predictive of their withdrawal-induced anxious or depressive symptoms (Burgess et al., 2002; Covey et al., 1990; Pomerleau et al., 2000).

However, not all studies include ND as a covariate, which could be problematic: Dacomitinib if ND is positively correlated with psychopathology (as it is in the current study), predictive value could be erroneously attributed to psychopathology. The use of co-twins�� phenotypes as instrumental variables in the current analyses enables us to distinguish between our two hypotheses regarding outcome. The intraindividual analyses indicate that people with a lifetime history of MD or GAD have significantly higher levels of ND than do individuals without such a history.