The US Food and Drug Administration issued separate warnings for suicidality with antidepressants and antiepileptic drugs in the past 5 years. This study describes methods for examining the association of these agents with suicide attempts and suicide deaths in more broadly generalizable samples than examined by the US Food and Drug Administration. An observational study of mood disorders was examined that includes three decades of prospective assessments. Because of sample size differences, two distinct longitudinal implementations of the propensity adjustment are used in separate analyses of antidepressants and antiepileptic drugs. Propensity score quintile-stratified safety analyses were used with the large antidepressant data set; whereas, propensity score matched safety analyses were used with the smaller antiepileptic drug data because stratification was not feasible. In each case, mixed-effects survival models compared the safety of participants when receiving the respective class of medication to periods when they did not receive that medication. When participants were more severely ill, they were significantly more likely to receive either class of psychotropics. Propensity quintile-stratified safety analyses found that risk of suicide attempts or suicides was significantly reduced when participants received antidepressants. In contrast, propensity score matched safety analyses found neither significant risk nor protection from suicidality among participants receiving antiepileptics. Copyright © 2012 John Wiley & Sons, Ltd.