title: Inter- and intraindividual pharmacokinetic variations of mirtazapine and its N-demethyl metabolite in patients treated for major depressive disorder: a 6-month therapeutic drug monitoring study.
abstract: Mirtazapine pharmacokinetic (PK) data from patients on long-term treatment for major depression have never been investigated. For this reason, in a large naturalistic outpatient study (prospective, multicenter, open-labeled, and noncomparative) conducted in Sweden in the period 2000-2002, one of the main objectives was to outline the inter- as well as intraindividual PK variance of mirtazapine and demethylmirtazapine serum concentrations in a patient cohort treated up to 6 (optionally 12) months. A total of 192 male and female outpatients aged 18 years or older were included. Serum samples of mirtazapine and demethylmirtazapine were collected, by the means of therapeutic drug monitoring, at weeks 1, 4, 8, and 24 (52). Altogether 683 serum samples were analyzed. A pronounced interindividual variability of mirtazapine and demethylmirtazapine, and the demethylmirtazapine/mirtazapine ratio was seen. The coefficient of variation was about 38%, 33%, and 36%, respectively. The intraindividual variation over time was low, about 20% on all variables. At the population level, no accumulation of mirtazapine, demethylmirtazapine, or change of the demethylmirtazapine/mirtazapine ratio was observed over time. Women had significantly higher dose-corrected concentrations of mirtazapine and demethylmirtazapine and demethylmirtazapine/mirtazapine ratio than men. Patients above 65 years of age had higher concentrations than their younger counterparts. Among patients with adverse events, lower demethylmirtazapine concentrations were observed than in patients with no adverse events. Patients on multiple drug treatment had higher dose-corrected mirtazapine and demethylmirtazapine serum concentrations than patients taking only mirtazapine. Weight and BMI had a significant negative correlation with demethylmirtazapine concentrations and with the demethylmirtazapine/mirtazapine ratio. Continued efforts are warranted to perform PK studies in a natural clinical setting to learn and understand inter- and intraindividual PK variances in real patients treated for longer periods of time. For mirtazapine as well as for most antidepressant drugs only relatively short term PK is available. To help clinicians improve their treatment of patients with major depressive disorder, the possible implications on the PK with a long-term treatment are important to study.
authors.affiliation: Department of Medicine and Care, Division of Clinical Pharmacology, Linköping University, Linköping, Sweden. margareta.reis@klinfarm.lu.se
authors.forename: Margareta
authors.initials: M
authors.lastname: Reis
authors.forename: Jiri
authors.initials: J
authors.lastname: Prochazka
authors.forename: Ad
authors.initials: A
authors.lastname: Sitsen
authors.forename: Johan
authors.initials: J
authors.lastname: Ahlner
authors.forename: Finn
authors.initials: F
authors.lastname: Bengtsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D014151:Anti-Anxiety Agents / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D049628:Body Size / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism; D003975:Diazepam / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078785:Mirtazapine; D010045:Outpatients; D010076:Oxazepam / Q000627:therapeutic use; D011446:Prospective Studies; D012737:Sex Factors; D012907:Smoking; D013997:Time Factors; D016312:Treatment Refusal / Q000706:statistics & numerical data
chemical_list: D014151:Anti-Anxiety Agents; D000929:Antidepressive Agents, Tricyclic; D008803:Mianserin; D010076:Oxazepam; D000078785:Mirtazapine; D003975:Diazepam; C119256:demethylmirtazapine