The psychiatric disease itself is a cause of chronic metabolic complications. In addition, psychiatric patients are frequently smokers and receive psychotropic drugs worsening the risk of cardiometabolic diseases and leading to an increased mortality in comparison to the general population. The Nicotine replacement therapy (NRT) and varenicline are recommended treatments to help patients who want to quit smoking. These treatments have a modest efficacy, which may be enhanced by adapting them to the patients’ individual characteristics (e.g. demographic, clinical and/or genetic). Second generation antipsychotics have a propensity for inducing cardiometabolic side effects, especially weight gain, which can be important. Optimized prescription is therefore essential in order to maximize efficacy and tolerability of treatments. This can be reached by understanding the influence of environmental factors (e.g. comedications) and patients’ clinical susceptibilities such as age, gender and morbidities (e.g. cardiovascular diseases, hepatic or renal impairments) on the pharmacokinetics and pharmacodynamics of psychotropic drugs. To that purpose, this thesis aims at identifying opportunities to optimize the treatment by amisulpride and quetiapine, as well as NRT and varenicline, by the study of their pharmacokinetics, pharmacodynamics and pharmacogenetics. We identified factors influencing the effectiveness of NRT and varenicline, pharmacokinetics of varenicline, amisulpride and quetiapine as well as adverse events of amisulpride and quetiapine using standard clinical care data. In nicotine normal metabolizers determined by phenotyping or genotyping, we confirmed that varenicline have better quit rates compared to NRT. Women who smoke had higher response with varenicline over NRT. By using a population approach, varenicline pharmacokinetics was found to be influenced by body weight and a UGT2B7 genetic polymorphism. In adult and older patients, amisulpride pharmacokinetics was influenced by age and lean body weight, and the observed hyperprolactinemia, which can contribute to metabolic complications in the long-term, was not dependent on amisulpride concentrations within the therapeutic range. Quetiapine elimination was influenced by the concomitant administration of drugs inducing cytochrome P450 3A4 (CYP3A4) and its metabolic rate into norquetiapine was influenced by the CYP3A phenotype. Weight gain seemed to depend on quetiapine exposure. To conclude, the results of this thesis can be employed to optimize the efficacy and tolerability of NRT and varenicline in the general population and of amisulpride and quetiapine in the psychiatric population.