Double-blind comparison of sertraline and placebo in stroke patients with minor depression and less severe major depression.

BACKGROUND: Poststroke depression is a frequent condition and important to treat. The aim of this trial was to study the efficacy and tolerability of sertraline. METHOD: In 4 Swedish stroke centers, 123 patients (aged 70.7 +/- 9.9 years) were enrolled during the period September 1998 to January 2001 in a randomized, double-blind, placebo-controlled 26-week trial, at a mean of 128 +/- 97 days (range, 3-375 days) after stroke, if they fulfilled DSM-IV criteria of major depressive episode (N = 76) or minor depressive disorder (N = 47). The primary efficacy variable was a change in depression assessed by the Montgomery-Asberg Depression Rating Scale. The Emotional Distress Scale (EDS) was administered and the occurrence of emotionalism and quality of life (QoL) were assessed, as well as neurologic recovery. Efficacy analyses were intention-to-treat, short-term (week 6) and long-term (week 26). RESULTS: Of the 123 patients, 62 were treated with sertraline (50-100 mg/day) and 61 with placebo. Both groups improved substantially, with no differences between the treatments, either for major depressive episode or minor depressive disorder, or for short- or long-term antidepressant effect and neurologic outcome. EDS revealed a better outcome with sertraline at week 6 (p < .05). At week 26, the improvement in QoL was better in sertraline patients (p < .05) and there was a trend for emotionalism (p = .07). No serious side effects were seen. CONCLUSION: Poststroke depression as measured by a conventional depression rating scale improved over time irrespective of treatment. Positive effects specific to sertraline were identified in emotional distress, emotionalism, and QoL. The study indicates that poststroke emotional reactions comprise depression and other domains susceptible to pharmacologic therapy.

Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997.

Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (Cl) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for Cl CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower Cl CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower Cl CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.

Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting.

The prescribing of selective serotonin reuptake inhibitors for adolescents is extensive despite the fact that there are few pharmacokinetic (PK), efficacy, safety, or tolerability studies on this group. This study reports the PK findings from two trials in adolescents treated with citalopram (CIT) in naturalistic clinical settings: one retrospective and one prospective. The aim of our study was to describe serum concentrations of CIT, desmethylcitalopram (DCIT), and didesmethylcitalopram (DDCIT) (trough values in steady state) in adolescents in relation to daily dose and clinical information obtained from therapeutic drug monitoring request forms. Altogether, 44 patients younger than 21 years were scrutinized using this combined open-label approach. The main findings were that (1) there was a pronounced interindividual variability of serum CIT, DCIT, and DDCIT concentrations in all doses prescribed, in agreement with previous studies on adults; on correcting for dose, the coefficient of variance was about 50% for CIT, DCIT, and DDCIT; (2) the transformation of CIT to DCIT and of DCIT to DDCIT was similar within the dose range 20 to 60 mg/day; (3) there was a difference between the sexes on comparing the dose-corrected concentrations of CIT and DCIT, with girls presenting significantly higher values than boys; and (4) there was a strong dose-serum concentration relationship in three identified subgroups of adolescents: (a) nonsmokers (CIT, r(2) = 0.71; DCIT, r(2) = 0.81), (b) girls not taking oral contraceptives (CIT, r(2) = 0.75; DCIT, r(2) = 0.71,), and (c) girls in the last 14 days of the menstrual cycle (CIT, r(2) = 0.68; DCIT, r(2) = 0.64). In summary, the present study tentatively supports influences of sex, oral contraceptives, and smoking habits on the disposition of CIT in younger patients. Hence, future studies on CIT should assess these parameters.

Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting.

Olanzapine (Zyprexa) was approved for general prescription in Sweden in November 1996, and an HPLC-based therapeutic drug monitoring (TDM) routine for serum olanzapine (OLA) and its major metabolite, N-demethylolanzapine (DMO) was established in February 1997. During 1997 to 1999, a total of 753 TDM requests for a total of 545 Swedish patients was analyzed. Additional patient information on certain clinical variables was collected on specifically designed TDM request forms. After the exclusion process, samples from 194 patients were found to be eligible for further scrutiny. The concentration-to-dose (C/D) ratio for OLA varied 25-fold and that of DMO 22-fold. Women had a higher (P < 0.01) median C/D ratio for OLA than men (median, 7.2 nmol/L/mg vs 5.2 nmol/L/mg). Nonsmokers had a higher (P < 0.001) C/D ratio for OLA than smokers (median, 9.2 nmol/L/mg vs 4.0 nmol/L/mg). Smokers got higher prescribed (P < 0.05) doses of OLA than nonsmokers did. In the group with reported side effects, the median serum OLA concentration was 22% higher (P < 0.05) than in the group without side effects. Patients co-medicated with carbamazepine had a 71% lower median C/D ratio for OLA than patients on OLA monotherapy. The present TDM-based follow-up suggests that the influence of gender, smoking habits, and certain drug interactions may need to be considered for optimal dosage of OLA. TDM may be used for this purpose more readily in the future.

Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting.

When Efexor (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n = 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.