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We present a systematic study on the interaction potential of lamotrigine, with focus on psychoactive drugs. A review of routine serum concentration measurements of lamotrigine performed in our laboratory yielded a total of 1733 serum samples from 829 patients (530 women, 299 men) suitable for statistical analysis. Main results for the whole study population were (median; interquartile range in parentheses): dose, 200 (100-300) mg; serum concentration, 2.97 (1.82-4.74) μg/mL; Lamotrigine serum concentration-to-dose ratio (LTG-CDR), 14.8 (9.9-24.6) (ng/mL)/(mg/d). A linear mixed model, allowing multiple observations from the same patient, was used to identify and quantitate the effect of factors influencing the LTG-CDR. In addition to age and gender, a total of 35 different comedications (25 drugs used in psychiatry as well as 10 other drugs) were evaluated. With women younger than 70 years as the reference group, factors found to lower the LTG-CDR significantly were: male gender and comedication with carbamazepine, ethinylestradiol, fluoxetine, lithium, phenytoin, phenobarbital, or topiramate. Factors associated with a significantly higher LTG-CDR were: age ≥70 years, and cotreatment with valproate. No antidepressants other than fluoxetine and none of the antipsychotic drugs included were associated with an altered LTG-CDR. Concerning pharmacokinetic drug interactions, we conclude that lamotrigine can be safely combined with most psychotropic drugs.