Pharmacokinetics of antidepressant drugs : naturalistic and clinical trials

Abstract: Depression is a major public health problem and it is predicted to be the second leading cause of disease burden by the year 2020. The pharmacological treatment period for major depressive disorder (MDD) is relatively long and sometimes prophylactic over many years. Despite the many drugs introduced on this indication in recent years, details in the drug kinetics linked to the many possible clinical scenarios arising in phase-IV have not been adequately assessed.The main objective of this thesis was therefore to focus on the posology of the frequently prescribed antidepressant drugs citalopram (CIT), sertraline (SERT), paroxetine (PAR) and venlafaxine (VEN) in terms of trough level serum concentrations of the parent compound and metabolite(s) under steady state conditions. Therapeutic Drug Monitoring (TDM)-based bioanalytical data were to be linked to clinical information obtained on patients in naturalistic or controlled clinical trial phase-IV settings for evaluation of the inter- as well as intraindividual PK (pharmacokinetic) variance. Specific aims were to identifY and analyze subgroups with possibly deviating PK such as adolescents, elderly patients, and the differences between the sexes. From a controlled trial setting during a six months period a possible serum concentration-effect relationship should be searched for, as well as testing the applicability of a novel type ofTDM procedure based on the metabolite/parent compound ratio to explore both total and partial pharmacological noncompliance.Studies I-III were applied on the naturalistic TDM-based trial design. In brief, study I contained 44 adolescents treated with CIT. Study II evaluated trough values in steady state in 749 patients treated with CIT, and study III describes the same parameters for 187 patients treated with VEN. Results revealed that interindividual PK-variations were pronounced for all compounds on all dose levels, but the intraindividual variations were low. Adolescents seemed to have CIT values similar to adults, but old age was correlated with higher dose-corrected serum concentrations of both CIT and VEN. All studied compounds displayed differences between the sexes. Polypharmacy affected the metabolism of CIT and VEN as did smoking.Study IV contained 353 patients treated with SERT or PAR in a prospective, randomized multi-center trial with up to eight serum samples each over six months. In study V the TDM-based "compliance method" was tested on the SERT population from the study cohort. Results revealed that no serum concentration - clinical effect relationship could be found for either PAR or SERT. It was observed that the TDM compliance method seemed to detect not only total but also significant partial non-compliance.In conclusion, the present thesis describes the possibility for making further PK-assessments on antidepressant drugs commonly prescribed. Thus, by building up drug specific TDM databases in naturalistic clinical phase IV-trials, combined with a structured data analysis a detailed retrospective follow up on the PK of the drugs coming into play in real life emerged. Taken together with the PK-data obtained from a prospective, randomized trial, the overall significance of this thesis may be to forward a new strategy for TDM -related postmarketing surveillance studies. This strategy may also be of interest to explore for other psychoactive drugs as well as for other new drugs commonly used on lager patient groups on chronic medications but outside psychiatric indications.