Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine

Summary On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day.During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30–100 nmol · l^–1) but not during quinidine.It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.     

Effects of psychotropic drugs on the sleep-wakefulness cycle of the developing kitten

The effects of psychotropic drugs on the sleep-wakefulness cycle were studied in 70 kittens during their growth period from 1 to 28 days of age. Recordings of EEG, EMG of posterior neck muscles, and respiration were made as well as observations of behavior. Neither imipramine nor chlorpromazine decreased percent time of wakefulness in kittens until they were 16 to 18 days of age when decreases first occurred as in mature cats. These two drugs also depressed the percent time of activated sleep and increased that of slow-wave sleep, both actions being least prominent in newborn kittens 1 to 3 days old and becoming more marked thereafter. Propericiazine diminished activated sleep time and increased slow-wave sleep time, these changes being least marked in newborn kittens. This is the only drug that did not decrease the percent time of wakefulness. Haloperidol is the only drug that did not diminish activated sleep time; slow-wave sleep time, however, was increased and the percent time of wakefulness decreased. These effects were not observed until 16 to 18 days of age. In general, for all drugs studied, the effects were less marked in the younger subjects. Moreover, the drug effects on activated sleep were established earlier than those on wakefulness.     

Clomipramine and imipramine in obsessive-compulsive disorder

Twenty-three outpatients with primary obsessive-compulsive disorder (OCD) were started in a 12-week double-blind clinical trial of clomipramine (CLI) (n = 11) and imipramine (IMI) (n = 12). There was no placebo and no crossover. After 6 weeks of treatment, data on 19 subjects (9 CLI, 10 IMI) were available. After week 12, the sample was reduced to 16 patients (8 CLI, 8 IMI). At both time points, OCD symptoms showed modest reductions (in comparison with the pretreatment baseline) in both CLI and IMI groups. Both drugs showed a major antidepressant effect. Analyses accounting for the differences in the baseline levels indicated a somewhat superior effect of CLI over IMI on OCD as well as depression. The effect of CLI and IMI on OCD was independent of the initial severity of depression. There were no clear differences in the safety of the treatments.     

Severity of depression and benzodiazepine comedication in relationship to efficacy of antidepressants in acute trials. A meta-analysis of moclobemide trials

The severity of depression at baseline, measured by the 17-item Hamilton rating scale for depression (HAM-D), was analysed as a predictor of the response to treatment, with response being defined as a 50 per cent improvement on the HAM-D or a good/very good outcome on the clinical global assessment over four weeks treatment. There is a good correlation between the two outcome measures (r = 0.67), but the question of the optimal outcome measure in very mild depression remains unsolved. The meta-analysis was based on 2684 patients from a data pool of double-blind trials carried out with moclobemide compared to placebo and/or standard antidepressants. The placebo response rate was high (40 per cent) in very mild depression (HAM-D < 16) and low (12 per cent) in moderate and severe depression. The reverse was true for moclobemide and imipramine. They showed a relatively lower response rate in cases of very mild depression but an equally good response in mild, moderate and severe depression. Co-medication with benzodiazepines increases the response to placebo treatment and decreases the power of a comparative trial considerably. Benzodiazepines were more frequently given to patients who had been pretreated with an antidepressant before entering an experimental trial. When analysing the outcome of antidepressant drug trials, it is recommended that investigators take into account pretreatment, co-medication and baseline severity.     

Prepulse inhibition as a screening test for potential antipsychotics

Startle response amplitude is greatly reduced by a low intensity pulse presented 100 msec prior to the startle stimulus. The magnitude of this prepulse inhibition (PPI) is reduced in schizophrenic patients. In rats, apomorphine disrupts PPI; haloperidol antagonizes apomorphine's effects. We tested the antipsychotic drugs haloperidol, chlorpromazine, clozapine, and risperidone, and the non-antipsychotic psychopharmacological agents diazepam, buspirone, and imipramine for their ability to antagonize apomorphine's effects on PPI of the acoustic startle reflex. Haloperidol, chlorpromazine, and risperidone antagonized apomorphine's blockade of PPI. Clozapine antagonized apomorphine's effect only at a dose that decreased startle amplitude by 82%. Imipramine and diazepam did not antagonize apomorphine's effect at behaviorally relevant doses. Buspirone weakly antagonized apomorphine blockade of PPI, but, like apomorphine, disrupted PPI when given alone. These results suggest that this PPI test may provide a useful screening procedure for compounds wtih antipsychotic activity. However, the lack of a robust clozapine effect needs to be investigated.     

Comparison of the serum levels in primary non-agitated depressed out-patients treated with imipramine in combination with placebo, diazepam or dixyrazine

Sixty-three non-agitated depressed out-patients were selected according to the Feighner-Robins-Guze criteria for primary depressions for a double-blind, between-patient randomized study for an 8 week duration. All the patients were treated with imipramine following a fixed dose schedule for the first 2 weeks and thereafter according to clinical response (100-200 mg/day). This treatment was combined with either placebo, diazepam (10 mg/day) or dixyrazine (50 mg/day). The serum concentration of imipramine both at 2 weeks and later was significantly higher (P less than 0.05) in the group treated with dixyrazine than in the other two groups. In the group treated with diazepam, the serum levels of imipramine and desipramine were significantly lower than in the placebo group. The serum concentrations of diazepam, desmethyldiazepam and dixyrazine were almost unchanged during the study. No significant correlation was found between the dosage and the serum concentration of imipramine or desipramine. The change in mean CPRS-score correlated neither with the imipramine nor with the desipramine serum levels, it did correlate but negatively with the degree of side effects. The degree of side effects correlated positively with the serum concentration of desipramine.     

3H] imipramine binding sites are decreased in platelets of chronic pain patients

Tritiated imipramine binding to whole platelets was measured in sixteen chronic pain patients not suffering from major depression and in a control group. Maximum binding was significantly lower in chronic pain patients than in the control group, whereas the binding affinity was not significantly different.     

A double-blind comparison of alprazolam vs. imipramine and placebo in the treatment of major depressive disorder

In a 6-week double-blind trial 129 outpatients with major depressive disorder received either alprazolam, imipramine or placebo. Dosage was adjustable from 0.5 mg alprazolam, 25 mg imipramine or two capsules placebo b.i.d. to 4.5 mg alprazolam, 225 mg imipramine or three capsules placebo t.i.d. Both active drugs were more effective than placebo according to all the rating scales used. Alprazolam and imipramine did not differ consistently except in the somatic symptom cluster on the Hamilton Anxiety Rating Scale. Mean final daily dosage was 2.7 mg alprazolam, 117.3 mg imipramine and 7.2 capsules placebo. Patients on alprazolam reported fewer side effects than patients on imipramine and approximately the same number as patients on placebo. Anticholinergic side effects were commonly associated with imipramine; drowsiness was the most frequent side effect with alprazolam.     

Antidepressants and the control of predatory behavior

The problem is raised whether the concept of the pharmacological control of predatory behavior of the rat (muricide) does apply to a carnivorous species, the ferret. Antidepressant drugs with differential potencies on either noradrenaline and/or serotonin uptake were applied: Fluoxetine (6 and 12 mg/kg orally), chlorimipramine (15 mg/kg orally) and imipramine (5 and 10 mg/kg orally twice a day over a period of 17 days). None of these drugs inhibited capture elicitation or any components of the predatory behavior. Since also maprotiline had failed to inhibit predatory behavior of the ferret it is concluded that the concept of the neuropharmacological control of muricide does not apply to the ferret. The substrates which govern predatory behavior in rodents and in carnivores are not homologous.     

Hyperpyrexia following psychotropic drug overdose

A case of overdose of tricyclic antidepressants associated with severe pyrexia is reported in a patient taking monoamine oxidase inhibitors, and its management described. The similarities to and differences from the malignant hyperpyrexia syndrome are discussed.