Fluvoxamine-tricyclic antidepressant interaction. An accidental finding.
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Biomedical subjects
Publications and source records attributed to G Allers.
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Nineteen major depressed inpatients were treated over three weeks with desipramine. Cardiac beta-adrenergic receptor sensitivity was evaluated by an isoproterenol test before and after the three-week treatment. Desipramine induced a beta-adrenergic sensitivity decrease in most of the patients: I 20 (isoproterenol dose necessary to increase by 20 beats/min. the basal heart rate) before treatment: 89 +/- 37 ng/kg (mean +/- SD); after treatment: 170 +/- 135 ng/kg; p(t) less than 0.03. Despite a linear relationship between pretreatment beta-adrenergic sensitivity and post-treatment clinical state, there was no relation between post-treatment cardiac beta-adrenergic sensitivity and therapeutic response or even desipramine plasma levels.
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The linearity of the (AMT) kinetics of amitriptyline has been tested in 135 depressed dosed twice daily by measuring plasma. Their (AMT) and nortriptyline (NT) levels under steady-state conditions. The AMT concentration/dose ratios at low and high dosages were not significantly different and there was a linear relationship between the dose ratios and the concentration ratios. No change in the metabolic ratio (AMT/NT) was observed between the two dosages. Although the results are consistent with linear AMT kinetics, there may have been nonlinear kinetics in some patients as the ratio between the concentration/dose ratios in them at low and high dosages was greater than one. Those patients were characterized by a low concentration/dose ratio at low dosage. No clinical adverse effect appeared in the study.
The authors present a prospective study of a rapid desipramine dose adjustment on the basis of a 24-hour plasma concentration after a single 150 mg dose. For this, they use a prediction table constructed from data in the literature showing strong correlation between steady-state plasma levels and 24-hour single-dose levels. Despite the fact that desipramine action is not always linear, the method appears to be feasible and valid. In an attempt to reach a 150 ng/ml level, the authors obtained steady-state levels ranging from 85 to 317 ng/ml, with 14 of the 19 patients in the range between 125 and 250 ng/ml. Moreover, 11 of the 19 patients received a daily dose of 250 mg or more desipramine from the third day of treatment onward; in ten of these cases, this dose had been adapted.
The authors studied the responsiveness of cardiac beta-receptors to isoproterenol, a noradrenergic agonist, in 29 depressed patients and 13 control subjects. They showed a significantly lower sensitivity in depressed patients as compared with the control subjects. Focussing on the group of depressed patients without antidepressant treatment in the month preceding the study (n = 15) in order to avoid a bias, the following significant results were obtained: cardiac beta-adrenergic receptor sensitivity was lower in patients suffering from endogenous depression than in those suffering from reactive depression (as classified by Newcastle Scale). There was a negative linear relation between cardiac beta-adrenergic sensitivity and the posttreatment clinical state (as expressed by the MADRS score) for the 9 patients who ended a 3-week desipramine treatment period.
The effects of valpromide on amitriptyline (AMT) and nortriptyline (NT) plasma levels were examined in 20 depressed inpatients. They all were treated with AMT, 125 mg once daily, and 10 patients also received 600 mg of valpromide daily after 10 days on AMT. In the 10 patients receiving valpromide in addition to AMT, the mean AMT level increased from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) and the mean NT level from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01). This increase was not related to valpromide metabolite plasma levels, nor to the age of the patients. The addition of valpromide to a stable AMT regimen may result in an increase of antidepressant plasma level with clinical implications.
The biotransformation modification of amitriptyline by phenothiazines has been studied in 65 depressive inpatients. Thirty-four of them were treated with oral amitriptyline and 31 with a combination of amitriptyline and phenothiazine. Urinary and plasmatic results showed a decrease in hydroxylated metabolites of amitriptyline (OHAMTc and OHAMT) in patients with added phenothiazine.
Urinary elimination of HVA, MHPG and 5-HIAA was studied in 22 depressed inpatients before and after 28 days of antidepressant treatment. Mean values did not change significantly during treatment, and were not related significantly to recovery in patients. Some marked changes in urinary metabolite levels were, however, observed in individual patients, and could be related to changes in their depression. The direction of change in urinary monoamine metabolites during treatment was associated with pretreatment levels, in that high pretreatment values tended to decrease whereas low pretreatment levels tended to increase.
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Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 mg/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug.
Valpromide is largely used in the therapy of affective disorders for its presumed thymoregulating activity. So, it is often associated with tricyclic antidepressant treatment. Previous clinical studies lead us to consider the possibility of an interaction between valpromide and tricyclic antidepressants, interaction which could result in an increase of antidepressant plasma concentrations. But no pharmacokinetic study has been realized up to now in order to clearly demonstrate such a phenomenon. The authors studied amitriptyline and nortriptyline plasma levels in two groups of ten patients receiving 125 mg amitriptyline, once a day, during 20 days. In the second group, patients also received 600 mg valpromide daily after ten days on amitriptyline. In the first group amitriptyline and nortriptyline plasma concentrations remained stable between the tenth and the twentieth day. In the second group, addition of valpromide resulted in a significant increase of antidepressant plasma levels: from 70.5 +/- 35 to 105.5 +/- 49 ng/ml (p less than 0.0003) for amitriptyline, and from 61.0 +/- 34 to 100.5 +/- 65 ng/ml (p less than 0.01) for nortriptyline.
The authors relate eight cases of amineptine dependency collected between 1980 and 1988 in 7 women and 1 man treated in the CHU of Besançon (France). The pharmacodependency appeared to be limited mainly to an abuse and a psychic dependence, i.e. a compulsive need to use the drug on a periodic (two cases) or continuing (six cases) basis in order to experience its psychomotor stimulant like effect. The used dosages ranged between 1,000 and 2,500 mg per day. The daily dose was divided into little doses, every hour for example. The induction modality was progressive during weeks or months and a stable dose period was then encountered. In one patient only, we observed a progressive increase of the dose without stabilisation of the dose. The withdrawal of amineptine was obtained without problem except in 2 cases where we observed clinical manifestations of anxiety, psychomotor agitation or bulimia during one day. Four years after the beginning, amineptine dependence was still present in 2 patients. In 4 patients we obtained an interruption of the amineptine pharmacodependency for one to three years. We did not see again the two remaining patients. In two cases, the main diagnosis, according to DSM III, was a major personality disorder (borderline). In the six other cases the diagnosis was a bipolar affective disorder (including four cases with only hypomanic episodes only). In these six patients the main characteristic of their affective illness was the association with other psychiatric disorders, especially personality disorders, such as borderline personality in one case and atypical personality with uncontrolled behavior as the main feature, in the 5 other patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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It is common clinical experience that depressed patients comply poorly with their treatment schedules. In a retrospective study, the authors studied the compliance with the tricyclic antidepressant treatment (TCA) in 1,023 in-patients and evaluated the frequency of the plasma levels under or above the therapeutic range, following a first prescription of TCA. To describe the adherence to the TCA regimen, the investigators have classified patients as either "compliant" or "bad compliant" on the basis of two different arbitrary dividing points: plasma levels of tertiary OR secondary amine lower than 20 ng/ml, or plasma levels of tertiary AND secondary amine lower than 20 ng/ml. The antidepressant plasma levels were measured, on steady state conditions, using a gas chromatographic method. The incidence of bad compliance ranged between about 2.5 and 10%, depending on the criteria used, the incidence of plasma levels under or above the therapeutic window ranged respectively between 26 and 54%-4 and 24%. The results from this study should encourage TCA plasma level measurements.
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