Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described. Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study. The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype. The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug. Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

La prescription médicamenteuse est l’un des principaux outils thérapeutiques utilisé par le médecin. Si la médecine somatique décline sa clinique selon l’enchaînement symptômes- diagnostic-traitement, la psychiatrie se démarque d’une telle linéarité. En effet, bien qu’elle se soit calquée sur le modèle médical depuis la découverte des psychotropes en 1952, elle relève d’une clinique spécifique : en psychiatrie, d’une part le symptôme constitue une adresse à l’Autre, il contient donc une dimension relationnelle essentielle, d’autre part, le soin psychique implique une participation active du sujet, toute thérapie étant aussi auto-thérapie. La neuropharmacologie, en plein essor depuis 1952, propose un schéma thérapeutique se voulant plus scientifique car de plus en plus éloigné de la psychopathologie clinique. Le psychiatre est alors convoqué en tant que technicien de la prescription de psychotropes, le médicament se suffisant à lui-même d’un point de vue thérapeutique. Face à une telle évolution de la psychiatrie, comment préserver un abord clinique ?Notre pratique esquisse la possibilité de dégager l’acte de prescrire d’une technicité exclusive. En effet, sous certaines conditions, la prescription de psychotropes constitue un acte psychothérapeutique à part entière. Pour cheminer dans notre réflexion, nous sommes passés par le paradigme du pharmakon afin de complexifier la question du prescrire. La clinique suggère une possible alliance entre parole et médicament. Prescrire dans la parole, au-delà de la molécule, consiste à qualifier la substance par la parole, de façon à ce qu’elle devienne un médicament spécifique de la rencontre clinique. La molécule, guidée par la magie des mots, sera plus efficace. L’acte de prescrire se conçoit donc comme une création à deux, à réinventer à chaque nouvelle rencontre, le moment de la prescription relevant d’un cheminement intime du côté du clinicien. Ainsi, loin de s’exclure mutuellement, psychothérapie analytique et pharmacothérapie ont tout intérêt à croiser leurs regards sur la question du prescrire. Penser conjointement effet pharmacologique et relation clinique permet au clinicien de s’engager dans une authentique rencontre humaine avec le patient. La psychopathologie s’ouvrira, peut-être, sur de nouvelles perspectives thérapeutiques. / Prescribing medication is one of the main therapeutic tools used by physicians. If somatic medicine clinically acts according to a 'symptom-diagnosis-treatment' model, psychiatry does not follow this linear pathway. Although it has copied the medical model since the discoveryof psychoactive drugs in 1952, it possesses a specific clinical approach. First of all, in psychiatric care, the symptom is an address to the Other, it contains an essential social dimension. Moreover, it implies the subject's active participation, each therapy also being a self-therapy. Neuropharmacology, in full expansion since 1952, has taken a therapeutic scheme aiming at more scientificity by moving away from clinical psychopathology. Hence psychiatrists are seen as technicians of psychoactive drugs prescription, drugs being considered as self sufficient therapeuticaly. With regard to this evolution in psychiatric care, how can a clinical approach be maintained ? In practice, the act of prescribing can free itself from being exclusively technical. Prescribing psychoactive drugs can indeed, under certain conditions, be a true psychotherapeutic act. To guide us through this reflection, we used the pharmakon paradigm to make the issue of prescribing more complex. Clinical practice suggests a possible alliance between patients'words and medication. Beyond molecular action, prescribing through talking qualifies the substance by words, so it becomes a clinical-interaction-specific drug. The molecule, guided by the magic of words, will be more efficient. The act of prescribing is thus conceived as a creation made possible by two people, that must be reinvented at each encounter. The moment for prescribing is rather the fruit of the clinician intimate decision process. Thus, far from excluding each other, analytical therapy and pharmacotherapy would gain much from sharing their views on the issue of prescribing. Integrating both the pharmacological effect and the clinical interaction would allow clinicians to engage in an authentic human encounter with patients. Psychopathology may then open up to new therapeutic perspectives.

No description available.