cpp-199 and Depressive-Disorder

Forty-five patients suffering from a major depression were administered zimeldine, amitriptyline or placebo (15 patients in each group) in a double-blind controlled study. In the zimeldine group, seven of the 14 patients treated for more than one week presented a toxic syndrome consisting in a severe prostration, fever, myalgias and arthralgias. In all patients presenting this syndrome, laboratory analyses revealed an elevation of alkaline phosphatase and of aspartate and alanine aminotransferases and a decrease in white blood cell and platelet counts. Three patients presented a mild proteinuria and hematuria. Although an immunological mechanism cannot be ruled out, several characteristics of this reaction suggest the formation of a metabolite of zimeldine with direct cellular toxicity. The relatively high starting dose of 200 mg/day of zimeldine administered in the present study and the increment to 300 mg/day after only seven days might have contributed to the high incidence of toxic reactions observed.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Aspartate Aminotransferases; Depressive Disorder; Female; Humans; Leukocyte Count; Male; Middle Aged; Platelet Count; Time Factors; Zimeldine

Two studies of zimeldine in depressive illness are reported, one a double-blind, placebo-controlled trial, the other an open evaluation. In both studies, zimeldine was shown to have antidepressant properties. No simple relationship between plasma zimeldine or norzimeldine and clinical effect was demonstrated in eight patients treated for 6 weeks. Minor changes in electrocardiographic parameters were noted in some zimeldine patients. Side-effects attributable to zimeldine treatment were generally of mild to moderate severity and the drug was well tolerated. During the studies, one patient overdosed on zimeldine (5.2 g) and, although plasma concentrations were excessive, minimum side-effects were recorded. Two cases of suspected adverse drug reactions with zimeldine are described.

Topics: Adolescent; Adult; Aged; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Zimeldine

Topics: Adult; Amitriptyline; Antidepressive Agents; Brompheniramine; Clinical Trials as Topic; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Pyridines; Zimeldine

Plasma levels of maprotiline, zimelidine, and their respective demethylated metabolites were analyzed, and their relationship to the clinical response was examined, in 60 depressed patients given the drug treatment for 4 weeks. Significant correlation was found between zimelidine and norzimelidine levels (r = 0.531; p less than 0.05) as well as between the steady-state levels of total zimelidine and concentration of the drug 12 h after a single dose (r = 0.753; p less than 0.001). The ratios of drugs and their metabolites in individual patients remained remarkably constant throughout the study. Significant correlations between Hamilton Depression Rating Scale (HAMD) scores and plasma levels of total maprotiline (r = 0.613; p less than 0.05) or norzimelidine (r = -0.552; p less than 0.05) were observed in subgroups of retarded depressives on day 14, and between HAMD scores and norzimelidine levels in retarded depressives (r = 0.703; p less than 0.02) and all patients (r = 0.436; p less than 0.02) on day 28. Both maprotiline and zimelidine produced marked decreases in mean HAMD scores by the end of treatment, but the overall clinical response between the various subgroups was not significantly different (x2 = 3.15; df = 3). Responders and nonresponders to treatment could not be distinguished by mean plasma levels of drugs or their metabolites when all patients were considered. However, a significant difference was found in maprotiline levels between responders and nonresponders within a subgroup of retarded depressives.

Topics: Anthracenes; Chromatography, Gas; Depressive Disorder; Humans; Maprotiline; Psychiatric Status Rating Scales; Zimeldine

The therapeutic efficacy, tolerability and pharmacokinetics of zimeldine in elderly depressed patients were evaluated after administration of different doses of the drug in once daily evening doses. The doses of zimeldine were 100 mg during the first 2 weeks, 150 mg during the next 2 weeks and 200 mg during the last 2 weeks. Nine of the 11 patients (mean age 78 years) included in the study completed the 6-week treatment period, and all nine improved according to the Hamilton depression rating scale. The drug was well tolerated and the side effects were few and mild. No influence of clinical importance was noted in haematology, liver and kidney functions, EEG, blood pressure or pulse rate. Steady-state plasma concentrations of zimeldine, and its active metabolite norzimeldine, were achieved in most cases after 1 week of treatment in each dose regimen. The plasma concentrations increased linearly with the increase in dose. The maximal interindividual variations in plasma concentrations were 8-fold for zimeldine and 3-fold for norzimeldine . The plasma levels of both zimeldine and norzimeldine were higher in the elderly than reported earlier in younger patients. The ratio of norzimeldine/zimeldine concentrations was reduced in the elderly, indicating a reduction of the metabolic capacity. The results suggest that zimeldine can be administered in a once daily dosage regimen to elderly patients, but they should be given a lower dose than younger patients.

Topics: Aged; Depressive Disorder; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kinetics; Male; Zimeldine