Mirtazapine in combination with amitriptyline: a drug-drug interaction study in healthy subjects.

OBJECTIVE: To assess the steady-state pharmacokinetics of mirtazapine (30 mg/day orally) and amitriptyline (75 mg/day orally) during combined administration compared with that of either drug administered alone. To evaluate the tolerability and effects on psychometric tests of acute and subchronic administration of both drugs combined and alone. METHODS: In a single-blind, three-way cross-over study, 24 (12 male and 12 female) healthy subjects were randomly assigned to six different sequences of three 9-day treatments, i.e. racemic mirtazapine (30 mg/day), amitriptyline (75 mg/day) or the combination of these drugs. To control for acute pharmacodynamic assessments, during the first treatment period, a placebo group (n = 8; 4 females and 4 males) was added. Serial blood samples were drawn for plasma level measurements that were subsequently subjected to pharmacokinetic analysis. Psychometric tests assessed attentional performance, and a computer-assisted telephone questionnaire assessed self-ratings of drowsiness/alertness and sleep quality. RESULTS: Amitriptyline increased the C(max) of mirtazapine (+ 36%, p < 0.05) in male subjects only. Mirtazapine altered the C(max) of amitriptyline in both male (+ 23%, p < 0.05) and female (- 23%, p < 0.05) subjects. No changes were observed for other pharmacokinetic parameters. Metabolite parameters were not affected. Changes in parent compound levels mainly resulted from effects on absorption. The psychometric test results did not reveal significant changes between combined and single drug treatments. The telephone registrations of VAMRS and LSEQ did not show clinically relevant differences between the active treatments. CONCLUSION: Combined administration of mirtazapine (30 mg/day) and amitriptyline (75 mg/day) alters the pharmacokinetics of either compound to a minor extent. Adding one drug to the other and substituting one drug by the other had no major effects on tolerability. Nevertheless, caution is warranted when combining amitriptyline and mirtazapine.

The acute effects of the noradrenaline reuptake inhibitor Org 4428 on EEG sleep in healthy volunteers.

Drug-induced improvement of depression may be mediated by changes in sleep physiology. In earlier studies on sleep EEG changes during treatment with antidepressants in depressed patients it could not be excluded that sleep disruptions and changes in the amount and distribution of REM sleep play a role in the changes in the sleep EEG. Therefore knowledge of the effects of antidepressants on the sleep EEG in healthy subjects with non-disturbed baseline sleep is necessary. In a three-way cross-over study in 12 healthy volunteers two single doses of Org 4428 (a highly specific noradrenaline reuptake inhibitor), 25 and 100 mg, were compared with placebo. Sleep EEGs were visually analysed and EEG power of non-REM sleep was measured. The results indicate that sole noradrenaline reuptake inhibiting activity is a potent mechanism to affect sleep polygraphic variables in an antidepressant-like way, i.e. REM sleep suppression and lengthening of REM latency. Despite the increase in the duration of non-REM sleep, i.e. stage 2, no significant changes in EEG power in the range 1-15 Hz were found. Therefore, the acute REM sleep suppression of Org 4428 did not result in a simultaneous reduction of EEG power during non-REM sleep. To date, these and earlier results indicate that most drugs with antidepressant properties affect REM sleep variables consistently, whereas their effect on both sleep polygraphic and EEG power variables in non-REM sleep is unpredictable.

Factors that influence the outcome of placebo-controlled antidepressant clinical trials.

An important issue in judging the therapeutic potential of a new antidepressant drug is the effect size it generates in placebo-controlled trials which has to be compared with the effect of an active control. As this effect size tends to vary substantially it is not easy to predict the sample size in a clinical trial. We carried out two dose finding placebo- and imipramine-controlled, double-blind, multicenter and multinational trials (northern part of Europe) with a new psychotropic compound (NPC) currently being investigated in Phase II/III as a potential antidepressant in the indication major depressive disorder (MDD). Statistical analysis showed that the effect size of 150 mg per day imipramine was meager (1.04 points difference from placebo after 6 weeks according to total scores on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] based on the Intent-to-Treat group using last observation carried forward [LOCF] approach). To increase the discriminative power of the analysis we selected centers that were able to detect a difference of at least two points between imipramine and placebo on the HAM-D-17 total score at 6 weeks in the LOCF analysis (discriminative centers, DC). The other group of centers will be called non-discriminative centers (NDC). We found that 36 percent of centers were DC and recruited about 45 percent of patients. Further analysis revealed no statistically significant differences between the groups of centers concerning the important baseline characteristics of the patients. Also the pattern of reported adverse events did not differ between DC and NDC. We found a tendency for the DC to select more patients with recurrent illness, in particular with a previous good response to antidepressant therapy. The groups of centers differed in dropout rates for both active treatments (DC 19.3-20.4% vs. NDC 35.1-37.7%) but not for the placebo (DC 38.2% vs. NDC 30.5%) that could suggest that different treatment strategies were employed by different centers regarding the occurrence of adverse events with and without therapeutic effects.

Selecting investigators for a placebo controlled clinical trial: The most critical decision point?

We have analysed the trial results obtained in two placebo and imipramine controlled double blind studies with a new psychotropic compound. Statistical analysis as outlined in the protocol showed a rather meagre therapeutic effect of imipramine of 1.53 points difference on HAMD-17 total score in comparison to placebo. In order to increase the discriminative power of the analysis we performed a post hoc analysis selecting centres that were able to detect a difference of at least two centres points between imipramine and placebo on HAMD-17 total score at week 6 (selective centres). All other were called nonselective. The analysis revealed that there were no statistically significant differences between the two types of centres concerning patient characteristics except that the nonselective centres recruited less patients with previous good response to antidepressant treatment. There was also some difference in drop out rates in the active treatment group wich might indicate different treatment strategies in the two groups of centres that participated in this trials.

A double-blind multicentre comparison of mirtazapine and amitriptyline in elderly depressed patients.

A total of 115 elderly patients (60-85 years of age) with DSM III diagnosis of major depressive episode were randomly assigned to 6 weeks of treatment with either mirtazapine, 15-45 mg/day, or amitriptyline, 30-90 mg/day. Efficacy was assessed biweekly, using the Hamilton Rating Scale for Depression (HRSD) and Montgomery and Asberg Depression Rating Scale (MADRS) as primary outcome variables. The treatment with both drugs resulted in a similar reduction of total HRDS and MADRS scores, with no statistically significant differences between treatment groups at any assessment point or at endpoint. Statistically significant differences favouring amitriptyline were present according to CGI-Global Improvement Scale at endpoint, HRDS cognitive disturbance factor at weeks 2, 4 and 6 and endpoint and retardation factor at week 6. Adverse events were reported by a similar number of patients in both treatment groups. Additional research is needed to assess further the efficacy and tolerability of mirtazapine among elderly depressed patients.

The accuracy of early diagnosis and predictors of death in Alzheimer's disease and vascular dementia--a follow-up study.

A total of 87 patients with mild or moderate degree of dementia of the Alzheimer type (AD) or vascular dementia (VD) was identified (DSM-III criteria), and their cognitive capacity was evaluated by means of rating scales and psychometric tests. Three years later 30 patients (34%) were dead. Significantly more VD than AD patients died. Eight of the survivors declined to participate in a follow-up study, and 1 patient was excluded by mistake. Of the survivors, 17 had indisputably suffered cognitive decline during the follow-up period (4 VD and 13 AD, 35%). In the case of 11 patients (2 VD and 9 AD) cognitive decline remained doubtful, and 20 patients (9 VD and 11 AD, 42%) underwent no intellectual deterioration during the follow-up period. The results underline the problems of early diagnosis of dementia according to DSM-III criteria. For both sexes a high ischemia score and a low body mass index predicted death. A low score on a verbal fluency test predicted death for men but not for women, and a high difference between systolic and diastolic blood pressure increased the risk of death for men but not for women.

DGAVP (Org 5667) in early Alzheimer's disease patients: an international double-blind, placebo-controlled, multicenter trial.

We carried out a double-blind study of a vasopressin-related peptide, DGAVP citrate (Org 5667), in 115 patients with mild dementia, probable Alzheimer's type (DAT). Neither clinical rating scales nor psychometric tests revealed any improvement over 84 days with once-daily intranasal treatment with 2 different doses of DGAVP. We conclude that vasopressin-like peptides are not satisfactory therapeutic agents in DAT.

Late clinical testing of cognition enhancers: demonstration of efficacy.

The major difference between clinical trials for efficacy and Phase I trials is their duration; clinical trials of cognition enhancers, for example in senile dementia, require at least 6 months. Because no widely accepted treatment is available, the methodology for these trials is still in a the process of refinement. Double blind placebo-controlled trials are considered to be mandatory particularly by the FDA. Parallel group designs seem preferable and the so-called "enriched design" seems to possess advantages over more classical procedures. Outcome measures should include ratings by clinicians and family members. Self-reports are considered to be unreliable in Alzheimer patients but may be less problematic in AAMI. Psychometric tests of cognition and motor skill should also be included. An essential and pragmatic outcome criterion is, however, the quality of daily life.

Enhanced monoaminergic neurotransmission by desglycinamide-arginine-vasopressin in human subjects.

The effect of desglycinamide-arginine-vasopressin (DGAVP) on monoaminergic neurotransmission was studied in human subjects. Samples of cerebrospinal fluid (CSF) were collected during 240 min after DGAVP (2 mg) had been administered intranasally, and monoamine metabolites in CSF were measured with HPLC using electrochemical detection. Levels of homovanillic acid and 5-hydroxyindoleacetic acid increased (P less than 0.05) 150 min after DGAVP administration, whereas levels of 3-methoxy-4-hydroxyphenylglycol were stable during the time monitored. These results suggest that in human subjects the mechanism of action of DGAVP may involve dopaminergic and serotonergic systems.

Penetration of DGAVP (Org 5667) across the blood-brain barrier in human subjects.

To assess the penetration of desglycinamide-arginine-vasopressin (DGAVP, Org 5667) to the central nervous system, levels of DGAVP were measured in the lumbar CSF after peripheral administration. DGAVP (2 mg) was administered intranasally to 37 patients and CSF samples were collected from these patients 5 to 240 minutes later. Detectable levels of DGAVP in CSF could be found 5 minutes after administration, but levels declined rapidly during the next 90 minutes. The DGAVP levels in CSF correlated with plasma levels of DGAVP (r=0.586, p less than 0.001). According to these results, DGAVP may gain access to the central nervous system and may induce central effects.