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PubMed1987

Ca2+ modulators as antidotes to imipramine and neurotransmitter toxicity.

Flunarizine and nimodipine, Ca2+ modulators which exert antagonist effects against catecholamines and serotonin and have specific action on the brain, were used as antidotes to imipramine toxicity in the rat. Imipramine, a tricyclic antidepressant, inhibits synaptic reuptake of catecholamines and serotonin. Flunarizine administered concurrently with imipramine increased survival time significantly (p less than 0.04). After a lethal dose of imipramine (85 mg/kg) 5 out of 5 animals treated with flunarizine (2.37 +/- 1.21 mg/kg in divided doses) and 4 out of 5 animals treated with nimodipine (0.36 +/- 0.11 mg/kg) survived. The acute toxicity of imipramine might be related, in part, to drug-induced alteration in turnover of excitatory neurotransmitters which will induce intracellular Ca2+ accumulation and damage to vital organs. These toxic effects of endogenously produced neuroamines may be antagonized by nimodipine or flunarizine.

Animals↗
PubMed1998

Buspirone and imipramine for the treatment of major depression in the elderly.

BACKGROUND: The current study was designed to assess the safety and efficacy of imipramine and buspirone in the treatment of major depression in elderly depressed attendees of primary care practices. METHOD: 177 patients aged 65 and over (mean age = 72 years; range, 65-89) who met DSM-III-R criteria of unipolar major depression with a minimum Hamilton Rating Scale for Depression score of 18 were randomly assigned to 8 weeks of double-blind, placebo-controlled treatment with flexible doses of either imipramine or buspirone. RESULTS: Moderate to marked global improvement after 8 weeks of treatment (LOCF analysis) occurred in 70% of patients treated with imipramine, 61% of patients treated with buspirone, and 42% of patients treated with placebo (chi2 = 9.1, df = 2, p < .02). Drug treatment was well tolerated, with 77% of imipramine- and 61% of buspirone-treated patients completing 8 weeks of therapy. Imipramine/placebo differences were present from week 2 on, but buspirone/placebo differences occurred only at week 8. The presence of comorbid medical illness or concomitant use of nonpsychiatric prescription medications was not associated with poorer antidepressant response, increased adverse effects, or study attrition. CONCLUSION: Imipramine and to a lesser extent buspirone were found to be effective and well tolerated in the treatment of elderly depressed outpatients.

Age Factors↗
PubMed2006

Imipramine is effective in preventing relapse in electroconvulsive therapy-responsive depressed inpatients with prior pharmacotherapy treatment failure: a randomized, placebo-controlled trial.

OBJECTIVE: To compare the efficacy of imipramine versus placebo in preventing relapse after successful electroconvulsive therapy (ECT) in depressive inpatients with pharmacotherapy treatment failure prior to ECT. METHOD: During a 6-month period, the incidence of relapse was assessed. Two centers, both inpatient units for treatment of depressed patients, participated in this trial. Patients with DSM-IV-diagnosed major depressive disorder resistant to an anti-depressant and subsequent lithium addition and/or a monoamine oxidase inhibitor were included. Patients were randomly assigned to double-blind treatment with imipramine with adequate plasma levels (N=12) or placebo (N=15) after successful ECT. The mean imipramine dosage was 209 mg/day (standard deviation: 91.7, range: 75-325 mg/day). The main outcome measure was relapse defined as at least "moderately worse" compared with baseline score on the Clinical Global Impressions-Improvement scale. Treatments were compared with survival analysis using the Cox proportional hazards model, including psychotic features and the score on the Hamilton Rating Scale for Depression (HAM-D) at baseline as prespecified covariables. Patients were enrolled in the study from April 1997 to July 2001. RESULTS: In the placebo group, 80% (12/15) of the patients relapsed compared with 18% (2/11) in the imipramine group. The Cox regression analysis showed a significant reduction in the risk of relapse of 85.6% with imipramine compared to placebo (p=.007; 95% confidence interval [CI]=24.6% to 97.2%) adjusted for the covariables. There was an 18% increase in the relapse rate (p=.032; 95% CI=2% to 36%) per unit increase in HAM-D score before the start of the trial; psychotic features had no significant effect (p=.794). CONCLUSIONS: Depressed patients with pharmacotherapy treatment failure may benefit from the prophylactic effect of the same class of drug during maintenance therapy after response to ECT.

Adult↗
PubMed1997

Imipramine blocks the transient outward potassium current in rat ventricular myocytes.

AIM: To examine the effects of imipramine on transient outward potassium current (I(to) in rat ventricular myocytes. METHODS: The patch-clamp whole-cell recording techniques were used. RESULTS: Imipramine resulted in a concentration-dependent inhibition of I(to) with the IC50 of 6.0 mumol.L-1 and a concentration-dependent acceleration of I(to) inactivation. The blocking showed no difference at different testing membrane potentials. Imipramine produced slight effects (about 3 and 4 mV, respectively) on steady-state activation and inactivation curves of I(to), and tended to prolong the recovery of I(to) from inactivation (tau control = 37 +/- 11 ms; tau drug = 58 +/- 17 ms), but not significant (n = 4, P > 0.05). The inhibitory effect of imipramine on Ito was increased when the prepulses were prolonged progressively from 0 to 120 ms. (tau control = 22 +/- 8 ms; tau drug = 14 +/- 5 ms). CONCLUSIONS: Imipramine blocked Ito in concentration-dependent but voltage-independent manners, and with "open channel blocking" properties.

Animals↗
PubMedDate not supplied

Imipramine-induced increase in the inhibitory effect of adenosine receptor activation in the hippocampus.

Imipramine, a tricyclic antidepressant, is one of the main drugs used for the treatment of depression. We investigated the effects of the repeated administration of imipramine (10 mg/kg po for 14 days, twice daily) on adenosine receptor-mediated actions using extracellular and intracellular recording techniques in the rat hippocampal slices. Adenosine and 2-chloroadenosine dose-dependently decreased the amplitude of population spikes and the slope of the field excitatory postsynaptic potentials (fEPSPs) evoked in the CA1 cell layer and apical dendrites of the CA1 cells, respectively, by stimulation of the Schaffer collateral/commissural pathway. As revealed by intracellular recording, a membrane hyperpolarization and a strong attenuation of excitatory synaptic transmission contribute to the decrease in the population spikes and fEPSPs induced by adenosine and 2-chloroadenosine. The repeated administration of imipramine enhanced the effect of adenosine (3 microM) and 2-chloroadenosine (0.15 microM) on fEPSPs while the inhibition of population spikes was not changed. When higher concentration of 2-chloroadenosine (0.25 microM) was tested, repeated imipramine administration enhanced its inhibitory effect on population spikes but not on fEPSPs. The present report provides evidence that the inhibitory effect of adenosine receptor activation in the hippocampus is enhanced by repeated treatment with imipramine.

2-Chloroadenosine↗
PubMed1975

Influence of extrahepatic cholestasis on metabolism and biliary excretion of imipramine.

Seven days after bile duct ligation, rat receiving 80 mg of 14-C-imipramine/kg i.p. excrete less than 2 per cent of the dose as total drug (imipramine plus metabolites) within 2h through a bile fistula. In rats without cholestasis, the biliary excretion accounts for 15 per cent of the dose. The percentage of the dose found in liver, lung, brain, and blood does not differ from that found in bile fistula rats without prior bile duct ligation. The conjugates of the hydroxylated imipramine metabolites account for 33 per cent of the total drug excreted through bile after bile duct ligation as compared with 88 per cent in rats without bile duct ligation. The remaining 67 per cent of total drug are excreted as desmethylimipramine, imipramine-N-oxide and imipramine at about equal parts. Hepatic microsomal N-demethylating enzyme activity after bile duct ligation is decreased as well as the content of microsoma cytochrome P-450. A concomittant complentary appearance of the metabolically inactive cytochrome P-420 is observed.

Animals↗
PubMed1975

Effects of perphenazine on imipramine metabolism in man.

In previous studies we have shown that perphenazine inhibits the metabolism of nortriptyline and imipramine. In this study the metabolism of 14C-imipramine and 14C-desipramine was studied before and during treatment with perphenazine. Studies on the imipramine and desipramine metabolites in urine showed that the major effect of perphenazine is an inhibition of the 2-hydroxylation of imipramine and desipramine. This causes a decreased formation and excretion of non-conjugated and glucuronide bound hydroxy metabolites and accumulation of imipramine and desipramine. There was some relationship between the dose of perphenazine and the decrease in total urinary excretion but the individual variations in response were pronounced (2-3-fold).

Adult↗
PubMed1992

A double-blind comparison of paroxetine, imipramine, and placebo in major depression.

Results from a single-center, 6-week, double-blind, randomized prospective study of paroxetine, a selective serotonin reuptake inhibitor; imipramine; and placebo are reported. One hundred twenty outpatients with a moderate-to-severe DSM-III diagnosis of major depression were randomly assigned to one of the three treatments following a 4- to 10-day single-blind placebo washout period. Significant differences favoring paroxetine over placebo were present at endpoint on most major efficacy measures. Paroxetine was also well tolerated; 5 (15%) paroxetine and 5 (14%) placebo patients dropped out of the study due to adverse effects. Imipramine, however, was comparatively poorly tolerated. Forty-five percent of imipramine-treated patients (N = 17) dropped out of the study due to adverse effects. None of the efficacy measures showed a significant difference between imipramine and placebo. This finding was probably due to the high number of imipramine patients who discontinued before they could improve. These results support the efficacy of paroxetine in the treatment of major depression and underline its favorable side effect profile compared with tricyclic antidepressants.

Adult↗
PubMedDate not supplied

[Monitoring of the treatment of endogenous depression with imipramine and amitriptyline (preliminary report)].

Monitored treatment of a depressed phase of unipolar affective disorder was conducted in 11 female patients receiving imipramine and in 12 females taking amitriptyline. Patients were randomly assigned to one of the drug and in 6 patients the drugs were switched because of the lack of response to the first used compound. In the imipramine treated group a satisfactory response after 4 weeks of management (less than 6 points on Hamilton's depression scale) was observed in 6 patients and in amitriptyline treated group in 5 patients. Patients displaying a satisfactory response to amitryptyline had significantly higher--as compared to remaining patients in the group--plasma levels of the drug after two and four weeks of treatment. Such an association was not observed in patients treated wtih imipramine. Severity of depression and motor retardation before the treatment was similar both in patients with satisfactory and with poor response to imipramine as well as to amitriptyline. However the intensity of anxiety symptoms was higher in patients exhibiting poor response to treatment with amitriptyline and imipramine as well.

Adult↗
PubMed1986

Comparative efficacy of alprazolam, imipramine, and placebo administered once a day in treating depressed patients.

Ninety-eight outpatients with major depressive disorder were treated with alprazolam, imipramine, or placebo in a 6-week, double-blind study. Average doses were 3.67 mg of alprazolam and 167 mg of imipramine, given at bedtime. Fifty percent of patients taking alprazolam, 38.2% taking imipramine, and 17.7% receiving placebo improved their HAM-D scores by more than 50%. Eight patients on imipramine, 6 on alprazolam, and 1 on placebo dropped out because of side effects. The most common side effects for imipramine were tachycardia, constipation, light-headedness, and sedation; common side effects of alprazolam were light-headedness, sedation, and unsteadiness.

Adolescent↗
PubMedDate not supplied

Effects of genetic or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin monooxygenase and cytochrome P-450-dependent monooxygenases.

Imipramine metabolism has been studied in both type I (streptozotocin-induced insulin-deficient) and type II (genetically insulin-resistant) diabetes in mice. In both types of diabetes, the formation of imipramine N-oxide is increased. In type I diabetes, desmethyl- and 2-hydroxyimipramine are additionally increased. The inhibition of imipramine metabolism by anti-cytochrome P-450 reductase antibodies led to the conclusion that cytochrome P-450-dependent monooxygenases are not involved in the N-oxidation of imipramine. This metabolic route is only supported by the flavin monooxygenase, whose activity is increased by diabetes. The pharmacological implications of altered imipramine metabolism in diabetic states are discussed in relation to the drug metabolism in human diabetes.

Animals↗
PubMed1987

Increased alpha 1- and decreased alpha 2-adrenoceptor sensitivities upon chronic treatment with imipramine in mediating cardiovascular responses in pithed rats.

After chronic treatment with imipramine (20 mg/kg, i.p., twice daily for 14 days) the pressor dose-response curves to phenylephrine, methoxamine and cirazoline (alpha 1-adrenoceptor agonists) significantly shifted to the left with decreased PD50 values in pithed rats; however, the dose-response curve to Sgd 101/75, a selective alpha 1-adrenoceptor agonist was not affected. On the other hand, the alpha 2-adrenoceptor agonists such as B-HT 920, xylazine and clonidine produced a rightward shift for both the pressor (increased PD50) and cardioinhibition (increased ID50) dose-response curves in these rats. These results required treatment with imipramine over 2 weeks. Chronic treatment with imipramine has reduced the antagonism by prazosin of the pressor effect of phenylephrine when compared with the dose-ratios between the 2 groups. On the contrary, the antagonism by piperoxan of the cardioinhibitory effect of B-HT 920 was rather enhanced by the treatment, but that of the pressor effect of B-HT 920 was little changed. In cerebrocortical membrane fractions obtained from rats pretreated with imipramine, Ki of phenylephrine to displace [3H]prazosin was decreased, whereas that of clonidine and yohimbine to displace [3H]yohimbine was increased. In conclusion, it is demonstrated that after chronic imipramine treatment the peripheral alpha 2-adrenoceptors (both presynaptic and postsynaptic sites) as well as central alpha 2-adrenoceptors respond with a decreased sensitivity to the alpha 2-adrenoceptor agonists, and moreover, this treatment produces an increased sensitivity of the central and peripheral alpha 1-adrenoceptors to the alpha 1-adrenoceptor full agonists.

Adrenergic alpha-Antagonists↗
PubMed1985

The acute and the chronic effects of imipramine on the spontaneous motility in chick embryos.

The effect of imipramine on the spontaneous motility and development of chick embryos was studied from the 4th to the 19th day of incubation. On acute administration (a single dose of 12.5 of 25 mg/kg egg weight), imipramine already induced significant depression of spontaneous motility in 11-day embryos--an effect which increased significantly after the 15th day of incubation. The similar effect of imipramine in spinal embryos testifies to its direct action on the spinal cord and draws attention to certain details of the role of supraspinal structures of the CNS in the acute effect of imipramine. The chronic administration of imipramine showed that it had an almost 100% lethal effect from 4th to the 7th day of incubation. Between the 8th and the 10th day it caused longlasting depression of spontaneous motility. When it was administered between the 11th and 16th day of incubation, no significant effect on the development of spontaneous motor activity was found in chick embryos.

Animals↗
PubMed1977

Which tricyclic for depressed outpatients, imipramine pamoate or amitriptyline?

Fifty-seven neurotically depressed outpatients with sleep disturbance were randomly assigned to treatment with either imipramine pamoate or amitriptyline given in a single dose at bedtime in a double-blind study for four weeks. The results indicate that both imipramine pamoate and amitriptyline are equally effective in treating neurotic depression. The clinical lore that imipramine is more effective for retarded depression and amitriptyline for anxious, agitated depression was not supported by this study. Of special interest is the fact that the imipramine pamoate group had significantly earlier rising times, and a trend toward better quality of sleep. The side effect profiles of the two drugs were also remarkably similar in this population though more patients complained of side effects on amitriptyline than on imipramine.

Adjustment Disorders↗
PubMed1977

The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study.

In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20. For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression. During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies. L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.

5-Hydroxytryptophan↗
PubMed1986

Drug treatment of panic disorder: the comparative efficacy of imipramine, alprazolam, and trazodone.

Data from 74 patients with panic disorder were evaluated to determine the comparative efficacy of imipramine, alprazolam, and trazodone. All patients were treated with placebo for 3 weeks and were then blindly switched to active treatment for 8 weeks. Both imipramine and alprazolam were highly effective in reducing the symptoms of generalized anxiety, the frequency of panic attacks, and phobic avoidance. However, the time course of these effects differed; alprazolam demonstrated therapeutic properties during the first week, whereas the therapeutic efficacy of imipramine was not clearly apparent until the fourth week of treatment. Relative to imipramine and alprazolam, trazodone was not an effective treatment for panic disorder and was poorly tolerated; only 17 trazodone-treated patients completed at least 4 weeks of treatment, and only 2 patients were considered good or complete responders. These findings support the hypotheses that drugs that are efficacious in the treatment of panic disorders act by altering noradrenergic function and that drugs with primary actions on serotonin function are likely to be less effective treatments. The different time courses of therapeutic action of imipramine and alprazolam indicate that these drugs ameliorate panic anxiety via different mechanisms. The possible therapeutic applications of this observation are discussed.

Agoraphobia↗
PubMed1987

Analysis of 2-hydroxyimipramine in an imipramine-related fatality.

A fatality following ingestion of the tricyclic antidepressant imipramine (Novopramine), acetaminophen, and ethyl alcohol is described. Imipramine, desipramine, acetaminophen, and 2-hydroxyimipramine were quantitated by high performance liquid chromatography, and ethyl alcohol by gas liquid chromatography. Concentrations of imipramine, desipramine, 2-hydroxyimipramine, and acetaminophen were: in blood--9.0, 1.1, 3.9, and 11 mg/L; in urine--92, 14, and 42 mg/L (acetaminophen not quantitated in urine). Ethyl alcohol concentration in blood was less than 10 mg/dL and 105 mg/dL in the urine by headspace gas chromatography. These findings are compared to previous reports of imipramine-related fatalities. To our knowledge, this is the first fatality reported involving imipramine where analysis included quantitation of 2-hydroxyimipramine in blood and urine.

Acetaminophen↗
PubMed1986

Changes in socio-emotional behavior under imipramine treatment in normal and amygdalo-hypothalamic dogs.

The effects of imipramine on learned social responses were examined in ten dogs with dorsomedial amygdalar lesions and/or lateral hypothalamic lesions. Six of the ten dogs were also tested preoperatively. The social responses were instrumentally conditioned using social interaction with the experimenter as reinforcement (petting and verbal reassurance). In the non-lesioned dogs imipramine treatment produced a dose-dependent deterioration of performance during drug administration followed by a long-term amelioration of performance. In the lesioned dogs imipramine produced various changes in performance depending on the pretreatment level of responding. When the pretreatment level of performance was high drug administration resulted in a long-term deterioration, and when performance was poor imipramine produced a continuous and long-term increase. It is suggested that imipramine facilitates the recovery of performance, but suppresses well-performed responses.

Amygdala↗