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PubMed1985

High- and low-affinity binding components for [3H]imipramine in rat cerebral cortex.

The present study demonstrates that [3H]imipramine binds to both high- and low-affinity imipramine binding components on membranes prepared from rat cerebral cortex. Scatchard and computer analyses of saturation experiments using a wide range of [3H]imipramine concentrations (0.5 nM-50 nM) revealed the presence of two binding components. Inhibition experiments in which membranes were incubated with [3H]imipramine and various concentrations of unlabelled imipramine gave shallow inhibition curves with a Hill coefficient of 0.60 +/- 0.04. When dissociation rates of imipramine were studied, biphasic dissociation curves were obtained with apparent half-times of dissociation of 2.5 +/- 0.4 min and 18.5 +/- 2.5 min. Thus analysis of saturation, competition, and dissociation experiments indicate that [3H]imipramine binds to low as well as high-affinity binding sites in rat cortex.

Animals↗

PubMed1989

Comparative in vivo and in vitro study of the cardiac effects of midalcipran and imipramine.

Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-5) M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.

Action Potentials↗

PubMed1979

The relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in rabbits in vivo.

1. Conscious or barbiturate-anaesthetized rabbits were slowly infused intravenously with solutions of amitriptyline, imipramine, maprotiline or mianserin, usually until death occurred. 2. Amitriptyline produced death at the lowest dose, imipramine and maprotiline were intermediate while much higher doses of mianserin were required. 3. Convulsions were induced by the antidepressants in all conscious rabbits and the order of potency of the drugs in producing this effect was amitriptyline greater than or equal to imipramine greater than maprotiline greater than mianserin. 4. All four drugs produced a reduction in heart rate and blood pressure in the anaesthetized rabbits and the order of potency in this respect was amitriptyline greater than imipramine greater than maprotiline greater than mianserin. 5. All four drugs produced significant changes in the ECG compared with control rabbits. The P-R interval was lengthened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin) and the QRS complex was widened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin). 7. It is concluded that all four drugs show the toxic effects classically associated with tricyclic antidepressants but the relative toxicity amongst these agents varies considerably and is in the order amitriptyline greater than imipramine greater than maprotiline greater than mianserin.

Amitriptyline↗

PubMed1983

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.

Adult↗

PubMed1985

Effect of phenobarbitone on the distribution and elimination of imipramine in rats.

The effect of phenobarbitone on the steady state volume of distribution (Vdss) and the total body blood clearance (CLtot, b) of imipramine and the serum concentration of its metabolite, desipramine was examined. The serum disappearance of imipramine after an 8 mg kg-1 i.v. dose followed a biexponential decline in both control and phenobarbitone-treated rats while the concentration of its metabolite increased in the phenobarbitone-treated rats then rapidly declined compared with that in control rats. Since CLtot,b was nearly equal to the hepatic blood flow (QH), QH may be the rate-determining step of imipramine elimination. In the control rats the Vdss of imipramine was large at 19.9 litre kg-1. In the phenobarbitone-treated rats the pharmacokinetic parameters, biological half-life (t1/2) and Vdss significantly decreased to approximately 23-40% while CLtot,b increased to 126% of those in the control rats, although the latter difference was not statistically significant. The blood-to-plasma concentration ratios (RB) of imipramine and desipramine decreased in the phenobarbitone-treated rats. The urinary excretion ratios of imipramine and desipramine, to the dose of imipramine over 8 h, were less than 1.5% in both groups. These ratios were not significantly changed in the phenobarbitone-treated rats. It was concluded that the significant decrease in t1/2 of the phenobarbitone-treated rats may not be attributed to the changes in CLtot,b and/or in the urinary excretion, but mainly to the decrease in Vdss.

Animals↗

PubMed1998

Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients.

OBJECTIVE: This study examined whether a selective serotonin reuptake inhibitor (paroxetine) had comparable efficacy but greater tolerability than a tricyclic antidepressant (imipramine) in depressed patients with HIV infection. METHOD: Seventy-five HIV-positive patients (45% of whom had AIDS) were blindly and randomly assigned to receive paroxetine (N = 25), imipramine (N = 25), or placebo (N = 25) in a 12-week trial. The Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Clinical Global Impression scale, and the SAFETEE general inquiry (for safety and tolerability) were administered at weeks 2, 4, 6, 8, and 12. RESULTS: Fifty-six (75%) of the 75 patients completed 6 weeks and 34 (45%) completed 12 weeks of the trial. The mean daily doses of both paroxetine (33.9 mg) and imipramine (162.5 mg) were significantly more effective than placebo; they were comparably effective at weeks 6, 8, and 12 according to the intent-to-treat analysis and at week 8 according to the analysis for the subjects who completed the trial (for them, only imipramine was superior to placebo at week 12). There were significantly more dropouts due to side effects from imipramine (48%) than from both paroxetine (20%) and placebo (24%). CONCLUSIONS: Depressed patients with HIV infection responded to imipramine or paroxetine at a higher rate than to placebo irrespective of severity of immunosuppression. Because paroxetine was much better tolerated than imipramine, its overall effectiveness may be greater. However, because of the small study group and the high attrition rate, these findings cannot be generalized and may need replication in a larger study group.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Gender differences in treatment response to sertraline versus imipramine in chronic depression.

OBJECTIVE: The authors examined gender differences in treatment response to sertraline, a selective serotonin reuptake inhibitor (SSRI), and to imipramine, a tricyclic antidepressant, in chronic depression. METHOD: A total of 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were randomly assigned to 12 weeks of double-blind treatment with sertraline or with imipramine after placebo washout. RESULTS: Women were significantly more likely to show a favorable response to sertraline than to imipramine, and men were significantly more likely to show a favorable response to imipramine than to sertraline. Gender and type of medication were also significantly related to dropout rates; women who were taking imipramine and men who were taking sertraline were more likely to withdraw from the study. Gender differences in time to response were seen with imipramine, with women responding significantly more slowly than men. Comparison of treatment response rates by menopausal status showed that premenopausal women responded significantly better to sertraline than to imipramine and that postmenopausal women had similar rates of response to the two medications. CONCLUSIONS: Men and women with chronic depression show differential responsivity to and tolerability of SSRIs and tricyclic antidepressants. The differing response rates between the drug classes in women was observed primarily in premenopausal women. Thus, female sex hormones may enhance response to SSRIs or inhibit response to tricyclics. Both gender and menopausal status should be considered when choosing an appropriate antidepressant for a depressed patient.

Adult↗

PubMed2002

Reduction in preference for saccharin by repeated unpredictable stress in mice and its prevention by imipramine.

The present study set out to establish the chronic mild stress (CMS) animal model of depression in male CD-1 mice, a commonly used mouse strain. Mice were exposed to a series of mild stressors (e.g. soiled bedding, paired housing, cage tilt, white noise) presented in a continuous unpredictable fashion. Intermittently, CMS was discontinued and the mice were presented with both water and a palatable saccharin solution (0.1% w/v) in a two-bottle choice test overnight (15 h). Repeated exposure of these mice to the stressors led to a reduction in preference for the saccharin solution. This change in preference was attributed to an increase in the consumption of water rather than a decrease in the consumption of saccharin solution. Over time and with extensive testing, CMS no longer affected performance in the two-bottle saccharin preference test. Treatment with the tricyclic antidepressant imipramine (20 mg/kg i.p., once daily) had a varied effect on the CMS-induced change in preference for saccharin, dependent on the timing of initiation of imipramine treatment. In the first instance, following 5 weeks of CMS where a reduction in saccharin preference was established, treatment with imipramine for a further 5 weeks maintained the stress-induced deficit in saccharin preference. However, using a different approach, pre-treatment with imipramine once daily for 2 weeks, prior to onset of CMS, and co-treatment thereafter, attenuated CMS-induced changes in saccharin preference. Finally, when imipramine treatment was scheduled to begin with the CMS procedure, imipramine failed to prevent the CMS-induced reductions in saccharin preference. Changes in behaviour observed after exposure to CMS may be linked to a stress-induced deterioration of the sensitivity of the mice to a rewarding stimulus. Treatment with imipramine can reduce these behavioural changes but is only effective when given repeatedly prior to onset of CMS.

Animals↗

PubMed1979

Comparison of efficacy of amoxapine and imipramine in a multi-clinic double-blind study using the WHO schedule for a standard assessment of patients with depressive disorders.

A multi-clinic double-blind controlled study on amoxapine in comparison with imipramine, using the WHO Schedule for a Standard Assessment of Patients with Depressive Disorders, was performed and the data were analyzed with 111 patients. The assessment of severity of illness and overall improvement indicated clearly the superiority of the antidepressive effect of amoxapine to that of imipramine. The onset of antidepressive effect of amoxapine was clearly more rapid than that of imipramine, and in more than half of the patients in the amoxapine group the improvement was seen within four days following the drug administration. Amoxapine was superior to imipramine in terms of safety and usefulness. The side-effects due to amoxapine appeared less frequently and were less serious than with imipramine. The difference between amoxapine and imipramine was especially remarkable for hypotensive effect. The antidepressive effect of amoxaphine was superior to that of imipramine for almost all symptoms and signs. Amoxapine displayed an especially remarkable effect on psychomotor retardation, depressive feeling, anxiety and tension, somatic complaints and sleep disturbance.

Amoxapine↗

PubMed2001

Positive responses to imipramine in the popliteal lymph node assay are due to primary irritation.

The popliteal lymph node (PLN) assay has long been proposed as a tool to detect immunotoxicants with the potential to induce systemic autoimmunity. A major problem hampering the further validation of this assay is the need to rule out irritants that cause false-positive PLN responses. The anti-depressant, imipramine, has not been reported to induce systemic autoimmune reactions in treated patients, but has been repeatedly found positive in the PLN assay, suggesting that this is a false-positive response. To test this hypothesis, the effects of imipramine were compared to those of 50% ethanol in C57B1/6 mice. Footpad edema was evidenced in the few days after injection of both ethanol and imipramine. T-cell depletion using monoclonal antibodies against either CD4+ or CD8+ T-lymphocytes prior to the PLN assay did not influence the responses to either ethanol or imipramine. Cytokine (TNFalpha, IL-1alpha, IL-1beta, IL-2R, IL-6, IL-12 and IFN-gamma) fingerprinting of the PLNs after injection of ethanol and imipramine evidenced the same pattern of responses. These results indicate a closely similar pattern of responses following the footpad injection of either imipramine or ethanol. The conclusion can be drawn that imipramine induces positive responses in the PLN assay via primary (nonspecific) irritation.

Animals↗

PubMed1994

A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder.

Recent studies have shown that cognitive therapy is an effective treatment for panic disorder. However, little is known about how cognitive therapy compares with other psychological and pharmacological treatments. To investigate this question 64 panic disorder patients were initially assigned to cognitive therapy, applied relaxation, imipramine (mean 233 mg/day), or a 3-month wait followed by allocation to treatment. During treatment patients had up to 12 sessions in the first 3 months and up to three booster sessions in the next 3 months. Imipramine was gradually withdrawn after 6 months. Each treatment included self-exposure homework assignments. Cognitive therapy and applied relaxation sessions lasted one hour. Imipramine sessions lasted 25 minutes. Assessments were before treatment/wait and at 3, 6, and 15 months. Comparisons with waiting-list showed all three treatments were effective. Comparisons between treatments showed that at 3 months cognitive therapy was superior to both applied relaxation and imipramine on most measures. At 6 months cognitive therapy did not differ from imipramine and both were superior to applied relaxation on several measures. Between 6 and 15 months a number of imipramine patients relapsed. At 15 months cognitive therapy was again superior to both applied relaxation and imipramine but on fewer measures than at 3 months. Cognitive measures taken at the end of treatment were significant predictors of outcome at follow-up.

Adolescent↗

PubMed2004

Partial glucocorticoid agonist-like effects of imipramine on hypothalamic-pituitary-adrenocortical activity, thymus weight, and hippocampal glucocorticoid receptors in male C57BL/6 mice.

Abnormal hypothalamic-pituitary-adrenocortical (HPA) activity may provide clues to the neurochemistry of depression. Psychotic depression has one of the highest rates of elevated HPA activity and is most often responsive to the tricyclic class of antidepressants. Because successful treatment resolves HPA as well as psychiatric symptoms, we hypothesized, in light of evidence that tricyclic antidepressants can affect glucocorticoid receptor function, that these drugs would mimic glucocorticoid feedback inhibition of HPA activity. To test this hypothesis, we measured circadian nadir (morning) and peak (evening) as well as restraint stress-induced levels of plasma ACTH and corticosterone in adrenalectomized (ADX) and sham-ADX (Sham) male C57BL/6 mice after 8 wk of imipramine (20 mg/kg/d, ip) or saline treatment. Antidepressant efficacy was confirmed by decreased immobility in forced-swim testing. When glucocorticoids were low or absent, imipramine mimicked glucocorticoid action in inhibiting evening ACTH in ADX mice and tending to inhibit morning corticosterone in Shams. However, when glucocorticoid levels were high, imipramine appeared to interfere with feedback inhibition by increasing post-stress ACTH and tending to increase evening corticosterone in Sham mice. Imipramine also decreased thymus weight in ADX and increased thymus weight in Sham mice. Imipramine stimulated morning ACTH in ADX mice, possibly by mimicking facilitative effects of high glucocorticoids. Short-term imipramine treatment was capable of inducing nuclear translocation of hippocampal glucocorticoid receptors in ADX mice. We conclude that imipramine effects on glucocorticoid-sensitive endpoints in vivo resemble those of a glucocorticoid partial agonist.

Adrenalectomy↗

PubMed1989

Synthesis of C-labeled imipramine and its biodistribution in mice: a potential tracer for positron emission tomography.

A tricyclic antidepressant, C-labeled imipramine was synthesized by N-methylation of desipramine with 11CH3I to assist in the imaging of the human imipramine receptor by positron emission tomography. The radiochemical yield after purification of 11C-imipramine by high performance liquid chromatography was 28-63% at a specific activity of 26-53 Ci/mmol. The time required for synthesis, including purification was 30 min from the end of 11CH3I trapping. The organ distribution of 11C-imipramine was investigated in mice at various times after i.v. injection. The main accumulation of radioactivity was in the kidney, followed by the lung and the heart. In the brain, the radioactivity levels in the hypothalamus and striatum were the highest and remained constant, differentiating them from other portions of the brain. Furthermore, the result of a binding assay with 3H-labeled imipramine suggested that the regional distribution of 11C-imipramine in the same mouse brain correlated to that of the high affinity imipramine binding site.

Animals↗

PubMed1987

[Drug interaction of imipramine hydrochloride to the pharmacodynamics and pharmacokinetics of oxazepam].

In this report, we studied drug interaction between oxazepam and imipramine in rats. Oxazepam (20 mg/kg) and imipramine (20 or 50 mg/kg) were administrated orally. The oxazepam concentration in plasma, brain and liver were measured by the method of HPLC. The concomitant use of imipramine induced extension of the elimination half life (T 1/2 beta) and an increase of the area under the concentration time-curve (AUC) on the plasma concentration of oxazepam. With the concomitant use of imipramine, the AUC of oxazepam brain concentration increased approximately 1.42 to 1.56 in contradistinction to oxazepam alone. The anti-pentylenetetrazol effect of oxazepam at 1 hr after administration was increased by the concomitant use of imipramine, but there were no combination effects at 4 hr. The motor incoordination effect of oxazepam and diazepam was measured by the rotarod method. Oxazepam has little effect on the motor incoordination as compared with diazepam. The plasma protein binding of oxazepam was not changed by the combined use of imipramine both in vitro and in vivo. The pharmacodynamic effects of oxazepam were increased by the concomitant use of imipramine, and these effects were in reasonably good agreement with the change in brain concentration of oxazepam.

Animals↗

PubMed1987

Cardiovascular effects of paroxetine, a newly developed antidepressant, in anesthetized dogs in comparison with those of imipramine, amitriptyline and clomipramine.

The cardiovascular effects of various antidepressant drugs including paroxetine, imipramine, amitriptyline and clomipramine, administered intravenously, have been assessed. Paroxetine, imipramine, amitriptyline or clomipramine potentiated the response to norepinephrine (0.1 microgram/kg, i.v.) on systemic blood pressure, while paroxetine, imipramine and amitriptyline weakened the response to tyramine (30 micrograms/kg, i.v.). A marked decrease in systemic blood pressure was observed after large doses of each drug (3 and 10 mg/kg of paroxetine; 1-10 mg/kg of imipramine, amitriptyline or clomipramine); and half of the animals died following administration of 10 mg/kg of imipramine, amitriptyline or clomipramine. Paroxetine did not show a marked effect on heart rate at a dose of up to 3 mg/kg, although 0.1-3 mg/kg of imipramine, amitriptyline or clomipramine dose-dependently caused tachycardia. ECG disturbances were observed in animals administered 10 mg/kg of imipramine, amitriptyline or clomipramine; but in contrast, 10 mg/kg of paroxetine caused only slight changes in the ECG. Prolongation of atrio-ventricular conduction time was observed with all the drugs. It was concluded that the effects of paroxetine on the canine heart are more mild in comparison with other tricyclic antidepressants used, although its pharmacological features are essentially similar to those of other drugs.

Amitriptyline↗

PubMed2005

QTc prolongation associated with combination therapy of levofloxacin, imipramine, and fluoxetine.

OBJECTIVE: To report QTc interval prolongation associated with combination therapy including levofloxacin, imipramine, and fluoxetine. CASE SUMMARY: A 49-year-old white female presented to the emergency department with fever, aches, and pains for the past 3 days. She was diagnosed and treated for pyelonephritis in the hospital. Therapy included intravenous levofloxacin 500 mg every 24 hours and ceftriaxone 2 g every 24 hours, along with her medications upon admission, including imipramine 50 mg at bedtime and fluoxetine 10 mg/day. She was discharged after 5 days and returned the next day with chest tightness and shortness of breath. Upon the second admission, a 12-lead electrocardiogram showed a QTc interval of 509 msec. Levofloxacin was discontinued and the QTc interval fell to 403 msec. The patient was discharged 3 days later and instructed to consult with her primary care physician about discontinuing imipramine. DISCUSSION: This adverse drug reaction is thought to be a pharmacodynamic additive effect among fluoxetine, imipramine, and levofloxacin. Fluoxetine is a potent inhibitor of CYP2D6, and imipramine is metabolized by CYP2D6. Therefore, fluoxetine is able to increase the plasma concentrations of imipramine, leading to QT interval prolongation. Taken with imipramine, levofloxacin can lead to even greater prolongation of the QT interval. Based on the Naranjo probability scale, levofloxacin was possibly associated with cardiac arrhythmias in our patient. CONCLUSIONS: The use of levofloxacin alone, or more often in concomitant therapy with other medications that are known to prolong the QT interval, may cause QT interval prolongation; however, additional studies/case reports are needed to validate this conclusion.

Anti-Infective Agents, Urinary↗

PubMed1981

Cardiovascular effects of imipramine in intact dogs and isolated dog atria.

The effects of imipramine were investigated on the blood pressure and heart rate in the intact dog and on the atrial rate and contractile force in the isolated atrial muscle perfused with arterial blood of the donor dog. A continuous infusion of small doses of imipramine (30 micrograms/Kg/min, i.v., 30 min) produced an increase in the blood pressure and heart rate of the donor dog and the positive chronotropic and inotropic effects of isolated atria. These responses were blocked by treatment with propranolol. When a large dose of imipramine (1 mg/Kg/min, i.v., 15 min) was administered to the donor dog, the blood pressure fell and the heart rate initially increased and then decreased (i.e., 15 min later it decreased approximately 20% under the control level), and in isolated atria and the developed tension initially increased and 15 min later decreased but the atrial rate maintained over the control level. Examined doses of imipramine caused a potentiation of norepinephrine-induced action, and a large dose of imipramine significantly diminished norepinephrine-induced reflex bradycardia and/or frequently inverted to tachycardia. Moreover acetylcholine-induced reflex tachycardia was suppressed by imipramine treatment. From these results, it is concluded that imipramine may cause a hypotension mainly due to peripheral vasodilation, and may induce a suppression of baroceptive reflex mechanism.

Acetylcholine↗

PubMed1975

Effect of diphenylhydantoin on the biotransformation and biliary excretion of imipramine in rats.

1. Rats with biliary fistula excrete 18% of an intraperitoneal dose of [14C]imipramine (80 mg/kg) in bile within 2-5 h. Diphenylhydantoin (46 mg/kg) simultaneously administered intravenously decreases the biliary excretion of imipramine plus metabolites to 7% dose. With or without diphenylhydantoin, the highest biliary concentration of imipramine plus metabolites occurs 30-60 min after dosage. 2. With or without administration of diphenylhydantoin, 83% of the bile radioactivity is present as the conjugated 2-hydroxylated metabolites of imipramine. With imipramine alone, more conjugated 2-hydroxydesmethyl-imipramine than conjugated 2-hydroxyimipramine is excreted in the bile. Diphenylhydantoin reverses this order. 3. Administration of diphenylhydantoin does not significantly alter the concentration of imipramine plus metabolites in plasma, liver, lung and brain measured at five consecutive 30 min periods after dosage.

Animals↗