A double-blind comparison of the pharmacodynamic effects of single doses of lofepramine,amitryptyline and placebo in elderly subjects

Summary In a double-blind five-way cross-over study, six drug free healthy elderly subjects received single oral doses of lofepramine (70 mg, 105 mg and 140 mg), amitriptyline (50 mg) and matched placebo tablets.A dose related increase in plasma drug levels and pharmacological effects of lofepramine was observed. Lofepramine (140 mg) improved psychomotor performance (choice reaction time and letter cancellation), but no such change was seen with lower dose regimes or placebo. No significant differences between lofepramine and placebo were observed in other parameters measured.Amitriptyline, as expected, reduced salivary volume, produced drowsiness and impaired psychomotor performance. These changes correlated with plasma amitriptyline levels. The incidence of subjective side-effects with amitryptyline was also higher than that of lofepramine or placebo.In the dosage used, lofepramine exhibited no deleterious effect on the peripheral cholinergic system or psychomotor performance. This drug therefore is likely to be a relatively safe antidepressant for the elderly, but further investigations during long-term medication are required to verify these observations.     

A double blind comparison of lofepramine,imipramine and placebo in patients with primary depression

The results of a double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group. In particular, for severe and/or moderate occurrences of dry mouth, the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 (8 lofepramine vs 21 imipramine patients).     

Comparative clinical evaluation of lofepramine and imipramine. Psychiatric aspects.

Lofepramine, an imipramine analogue, was compared with imipramine in a multicentre, double-blind clinical trial. The 62 patients (31 in each of two treatment groups) had a depressive syndrome that normally would have been treated with a tricyclic antidepressant. These patients had not received any adequate treatment for this present depressive episode. After a wash-out period and once a week during treatment (up to 5 weeks), routine laboratory tests and electrocardiograms was done. The dosage was 50 mg t.i.d. for imipramine and 70 mg t.i.d. for lofepramine. Depression ratings with the Cronholm-Ottosson depression rating scale were performed before treatment and once weekly for 3 weeks and then in the 5th week. The last four ratings were combined with rating of side-effects. In the 5th week of treatment 15 out of 31 in the lofepramine group and 18 out of 31 in the imipramine group had recovered. This difference was not significant, nor did the median values of individual symptoms differ between the groups. The side-effects were moderate and the two groups only differed significantly in the items "dry mouth" and accommodation disturbances in favour of lofepramine. The drug compliance was checked by plasma levels of desmethylimipramine in the imipramine group, parent compound, and "apparent" desmethylimipramine in the lofepramine group. The relationship between plasma drug levels, the effect on noradrenaline uptake in vitro and amelioration discussed in Siwers et al. (1977) in this issue. The clinical outcome in the two groups did not differ significantly; interpretation of this result is discussed in relation to the reliability and selection of patients.     

Comparative clinical evaluation of lofepramine and imipramine. Pharmacological aspects.

A multicentre comparative clinical evaluation of lofepramine, an imipramine analogue, and imipramine has been made with double-blind technique and fixed dosage (lofepramine 70 mg t.i.d., imipramine 50 mg t.i.d.). Plasma was drawn after 3 weeks for determination of noradrenaline-uptake inhibitory capacity of the parent compound and/or its active metabolites. Plasma concentrations of lofepramine and desmethylimipramine (DMI) were determined in the same samples. The concentrations of lofepramine in the whole material were low (5-27 ng/ml) except for one patient who had a level of 53 ng/ml. In both groups of patients there was an almost 40-fold range in the plasma levels of DMI or apparent DMI. The patients were rated for severity of depression before treatment, then once weekly for 3 weeks and finally during the fifth week. For further information concerning the psychiatric aspects, see d'Elia et al. in this issue (1977). A significant correlation was found between the concentrations of DMI and the noradrenaline-uptake inhibitory capacity in the plasma samples. No correlations were found between uptake inhibitory capacity of plasma samples and the amelioration scores.     

Antidepressants in suicide: differences in fatality and drug utilisation

All forensic autopsy cases in southern Sweden in 1986–89 in which antidepressant drugs were found in the blood were assessed and the findings related to the sales of antidepressants as expressed as defined daily doses per 1,000 inhabitants per day. There was a total of 272 antidepressant-positive cases, which were divided in three groups: 1. suicide or possible suicide caused by antidepressant drugs, 2. suicide or possible suicide caused by other means (including other drugs and other toxic agents), and 3. other deaths.Amitriptyline was the agent most commonly involved in suicide or possible suicide caused by antidepressants, and it was also the most commonly sold antidepressant. When corrected for sales, trimipramine was most frequently involved as the causal agent.Conversely, despite frequent sales, lofepramine appeared only rarely to be involved. This may be related to lower toxicity of lofepramine, reduced lofepramine absorption at overdose and/or to differences in the administration of various antidepressant drugs to patients with differing degrees of risk of suicide.     

Pharmacokinetics of lofepramine in man: Relationship to inhibition of noradrenaline uptake

Summary The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desmethylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rat irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimpramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formedin vivo in man affect neuronal uptake of this amine. Lofepramine belongs to the group of tricyclic anti-depressants which preferentially inhibit noradrenaline uptake.Lofepramine = Leo 640 = N-methyl-N-[4-Chlorobenzoyl-methyl-3-(10.11-dihydro-5H-dibenz (b, t) azepin-5-yl]-propylamine     

Lofepramine and imipramine in unipolar depressed outpatients

This is a double-blind study involving 158 outpatients diagnosed ac-cording to the DSM-III as suffering from major depressive disorder. Both active drugs produced significantly more improvement than placebo on both physician and patient ratings, and lofepramine produced slightly less sedation and anticholinergic effects when compared with imipramine.