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PubMed1980

Effect of thioridazine on the first-pass kinetics of [14C]imipramine in perfused rat liver: interaction at hepatic binding sites.

1. The effect of thioridazine on the first-pass removal and hepatic metabolism of [14C]imipramine was examined in a single-pass rat liver perfusion system using a perfusate free of drug-binding components. Drug exposure continued for 45 min, and bile was collected and analysed during the final 15 min when approx. steady-state conditions were attained. 2. Thioridazine decreased the hepatic extraction ratio for imipramine, lowered the hepatic concentration (P < 0.1) and increased the effluent perfusate-to-liver ratios of imipramine. It is suggested that the increased imipramine in the effluent perfusate was due to competition of thioridazine for non-metabolizing binding sites in the liver rather than to inhibition of drug metabolism. 3. Thioridazine markedly increased desipramine concentrations in both liver and effluent perfusate. This may have resulted from decreased hepatic binding of imipramine, which made more free drug available for demthylation. Competition with thioridazine for hepatic binding sites also explains the increased diffusion of desipramine into the effluent perfusate. 4. Lower concentrations of 2-hydroxylated metabolites, especially 2-hydroxyimipramine, were found in bile when thioridazine was administered with imipramine. There was no evidence of inhibition of imipramine 2-hydroxylation. From bile-to-liver ratios, it is suggested that thioridazine and/or its metabolites inhibits glucuronylation of 2-hydroxyimipramine but not of 2-hydroxydesipramine.

Animals↗
PubMed1984

The metabolism and excretion of [14C]imipramine in an experimental hepatitis.

The effect of experimental hepatitis, induced by i.p. D-galactosamine, on the metabolism and excretion of [14C]imipramine in the rat is reported. The major consequence was an increase of the conjugated metabolites of imipramine excreted in urine, resulting in a four-fold increase in 2-hydroxyimipramine glucuronide and two-fold increases in 2-hydroxydesmethylimipramine glucuronide and 10-hydroxyimipramine glucuronide. The total excretion of 14C-labelled metabolites in urine of galactosamine-treated rats was 69% dose compared with 37% in untreated animals. Faecal excretion of [14C]imipramine metabolites was lowered from 68% dose in untreated animals to 27% in animals with induced hepatitis. Induction of a galactosamine hepatitis decreased markedly the biliary excretion of imipramine metabolites in bile duct-cannulated rats; 80% dose was excreted in bile in normal rats, and 35.5% in rats with hepatitis. Plasma clearance of imipramine, after i.v. dosage, was decreased by 60% and clearance of metabolites (excluding imipramine) by 40%, in galactosamine hepatitis; the pharmacokinetics changed from a two- to a single-compartment system reflecting decreased extraction and/or metabolism, by the liver. The clinical implications of these findings are discussed in relation to the hazard attending the use of imipramine in patients suffering from liver disease.

Animals↗
PubMed1982

Hemoperfusion for imipramine overdose: elimination of active metabolites.

The serum concentrations of imipramine and its pharmacologically active metabolites were followed during resin hemoperfusion for imipramine overdose. The initial serum concentration of 2-hydroxy-imipramine plus 2-hydroxy-desipramine was 13.3% of the total tricyclic antidepressant level (imipramine + desipramine + hydroxymetabolites). Despite high extraction ratio (greater than or equal to 0.75) and clearances (130--180 mL/min) for both imipramine and its metabolites, the calculated amount of drug removed was small. Only 0.91% of the estimated dose ingested was removed as imipramine, 0.52% as desipramine, and 0.33% as hydroxylated metabolites. While the hydroxylated metabolites of imipramine may contribute to its toxicity, it is unlikely that the small amount removed can explain reports of apparent clinical benefit from hemoperfusion.

Adult↗
PubMed2003

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder.

OBJECTIVE: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder. METHOD: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: 138 patients were treated with sertraline (76% female; mean age = 40 years) and 69 with imipramine (70% female; mean age = 40 years). The symptoms of both major depressive disorder and panic disorder responded significantly and equivalently to both drugs. Endpoint improvement with sertraline versus imipramine, respectively, on the MADRS was 11.1 +/- 10.8 versus 11.2 +/- 10.4, and on the Clinical Global Impressions-Improvement scale (CGI-I) was 2.1 +/- 1.3 versus 2.4 +/- 1.6. Among study completers, CGI-I responder rates were 88% with sertraline and 91% with imipramine. Treatment outcome was concordant for both diagnoses in approximately 70% of patients and discordant in approximately 30%. Overall, sertraline was significantly better tolerated with significantly fewer discontinuations due to adverse events (11% vs. 22%; chi(2) = 4.39, df = 1, p =.04). CONCLUSION: Both sertraline and imipramine were found to be highly effective treatments for both major depressive disorder and panic disorder, with sertraline showing significantly greater tolerability and compliance during long-term treatment than imipramine.

Adult↗
PubMedDate not supplied

Cholinergic mechanism in imipramine and morphine antinoception.

Antinociceptive effect of imipramine and morphine was studied in rats using tail flick method. Morphine and imipramine both increased the latency of tail flick response. Pretreatment with naloxone (0.5 mg kg-1) decreased the antinociceptive effect of morphine (1 mg kg-1) and imipramine (10 mg kg-1). In order to see if antinociceptive effect of morphine or imipramine involve cholinergic mechanisms, mecamylamine (1 mg kg-1) or atropine (1 mg kg-1) were administered 30 minutes before morphine (1 mg kg-1) or imipramine (10 mg kg-1) administration. Mecamylamine decreased the antinociceptive effect of morphine and imipramine (P < 0.001), whereas atropine had no effect. Thus, opiodergic and nicotinic systems appear to be involved in morphine and imipramine induced antinociception.

Adrenergic Uptake Inhibitors↗
PubMed1992

Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial.

A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.

Adult↗
PubMedDate not supplied

Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression.

The paper describes the effect of metyrapone supplementation on imipramine therapy in patients (with treatment-resistant unipolar depression) who fulfilled DSM IV criteria for major depression. Nine patients were enrolled to the study on the basis of history of their illness and therapy. Following 2 weeks of washout period, the patients were treated with imipramine twice daily (100 mg/day) for 6 weeks, and then metyrapone was introduced (twice daily, 500 mg/day), and administered jointly with imipramine for further 6 weeks. Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were used to assess efficacy of antidepressant therapy. Imipramine changed neither HDRS nor BDI score after 6 weeks of treatment when compared with baseline (before treatment). Metyrapone supplementation significantly reduced both HDRS and BDI scores after 6-week supplementation. Moreover, pharmacokinetic data indicate that metyrapone did not influence significantly the plasma concentration of imipramine and its metabolite, desipramine in the patients during joint treatment with metyrapone and imipramine, what suggests the lack of pharmacokinetic interaction. This preliminary study is the first demonstration of the benefit of metyrapone supplementation in imipramine therapy of treatment-resistant unipolar depression and suggests that a change in the level of neurotransmitters, hormones and immunological parameters, which are disturbed in depression, may contribute to the mechanism of the action of this drug.

Adult↗
PubMed2006

[Comparison of the effectiveness of two treatment strategies in inpatients with a depressive disorder. A double-blind study of imipramine followed by lithium addition versus fluvoxamine followed by lithium addition].

BACKGROUND: There is still uncertainty regarding the best treatment optionfor depressed inpatients and the best strategy to follow if patient response is insufficient. AIM: To compare the efficacy of imipramine and fluvoxamine in depressed inpatients who subsequently received lithium supplement in case of poor response. METHOD: After a drug-free period and four days of placebo use, patients were randomised either to imipramine or to fluvoxamine (phase 1); the antidepressant dosage was fixed according to a predetermined plasma level. The efficacy of the antidepressant was evaluated four weeks after the predetermined plasma level had been attained. If patient response was inadequate, the antidepressant was augmented with lithium (phase 2). Patient response to the lithium addition was evaluated three weeks after an adequate lithium level had been attained. RESULTS: The study involved 138 inpatients. At the end of phase 1, imipramine was found to be superior tofluvoxamine according to the Clinical Global Impression of Improvement. Remission was achieved by 6 (23%) patients on imipramine and by 10 (15%) patients on fluvoxamine; this difference was not statistically significant. At the end of phase 2, 41 (9%) patients on imipramine and 27 (40%) patients on fluvoxamine achieved remission, this significant difference demonstrating the superiority of the imipramine strategy. CONCLUSION: Imipramine with subsequent lithium addition is superior to a similar strategy with fluvoxamine.

Adult↗
PubMed1991

Long-term follow-up of chronic depression treated with imipramine.

A long-term follow-up assessment was conducted in 25 chronically depressed patients who had participated in a 6-week trial of imipramine to determine if imipramine responders would sustain a more favorable long-term outcome than nonresponders or noncompleters. Imipramine responders tended to remain on imipramine treatment throughout the follow-up interval and had a significantly better outcome. Eighty-nine percent of the imipramine responders met the criteria for recovery at follow-up compared with 31% in the comparison groups. Imipramine responders also fared significantly better at follow-up on measures of depression, global severity of illness, and social/vocational functioning. The results supported a more favorable long-term outcome in chronic depression patients who had responded to imipramine and suggest that maintenance therapy may be indicated and effective for this disorder.

Adult↗
PubMed1990

Vinpocetine therapy does not change imipramine pharmacokinetics in man.

The influence of vinpocetine on imipramine steady-state plasma levels was investigated in 18 healthy volunteers. Twenty-five mg imipramine were given t.i.d. for a total of 21 days, vinpocetine treatment was started on day 11 with 10 mg t.i.d. and continued until the end of the study. The AUC of imipramine plasma levels were obtained using consecutive imipramine plasma level determinations from samples drawn every 2 h from 8:00 a.m. to 8:00 p.m. by trapezoidal rule. AUCs of day 10 without and of day 21 during concomitant vinpocetine treatment were compared, demonstrating the independence of imipramine's bioavailability from concomitant vinpocetine treatment. There were no indications to assume a changed absorption of imipramine due to vinpocetine as would be reflected in Cmax and tmax values. Imipramine metabolization to the still effective metabolite desipramine shows a huge interindividual variability although it remains constant for the individual. The analysis of this parameter in the course of this study does not suggest that it is changed due to vinpocetine treatment.

Adult↗
PubMed1990

Adjunctive imipramine maintenance in post-psychotic depression/negative symptoms.

Fourteen schizophrenic or schizoaffective patients, who had had operationalized syndromes of post psychotic depression or negative symptoms unresponsive to adjunctive benztropine but responsive to adjunctive imipramine, completed a double-blind maintenance treatment trial of adjunctive imipramine vs. placebo. All patients were maintained on standing doses of fluphenazine decanoate and benztropine throughout. All six patients tapered to placebo relapsed into their depression-like, negative symptom state, whereas only 2 of 8 patients maintained on imipramine had such a course (p = .009, favoring imipramine maintenance). No patients maintained on imipramine relapsed into psychosis. These results suggest the advisability of maintaining adjunctive imipramine treatment, in conjunction with appropriate neuroleptic and antiparkinsonian regimens, in stable, syndromally defined, postpsychotic depressed or negative symptom patients initially responsive to adjunctive imipramine.

Adult↗
PubMed1989

A double-blind comparative trial of moclobemide v. imipramine and placebo in major depressive episodes.

Patients (n = 490) suffering from a major depressive episode according to DSM-III criteria were randomly allocated to groups receiving either moclobemide, imipramine, or placebo treatment. Subjects were treated as out-patients for 6 weeks. On overall assessment of efficacy and on results of the Hamilton Rating Scale for Depression, both moclobemide and imipramine were superior to placebo, but the differences between moclobemide and imipramine were not significant. Premature termination due to insufficient efficacy was more frequent with placebo than with moclobemide or with imipramine, these differences being significant. The overall assessment of tolerance clearly favoured placebo and moclobemide over imipramine. This was also reflected in the frequency of premature terminations due to poor tolerance, as well as in the frequency of adverse events, which were highest in the imipramine group. The only cardiovascular finding was an increase of the mean heart rate with imipramine, maximum at the end of week 1, while placebo and moclobemide displayed no relevant changes. There were no other important drug-related changes.

Adjustment Disorders↗
PubMed1985

5-methoxytryptoline and close analogs as candidates for the endogenous ligand of the 3H-imipramine recognition site.

3H-Imipramine labels with high affinity a site associated with the macromolecular complex of the serotonin transporter in brain and platelets. There is a good correlation between the potencies of drugs at inhibiting 3H-5HT uptake and at inhibiting 3H-imipramine binding. Dissociation experiments indicate that the site labelled by 3H-imipramine is not identical with the substrate recognition site of the serotonin transporter and thus, it appears that 3H-imipramine labels a modulatory site for the 5HT transport system. On this basis, the existence of an endacoid acting on the 3H-imipramine recognition site to modulate 5HT uptake is discussed. The possibility that 5-methoxytryptoline or a closely related analog may be the endogenous ligand for the 3H-imipramine recognition site is analysed on the basis of the fact that 5-methoxytryptoline is a potent inhibitor of 3H-imipramine binding that also inhibits 3H-5HT uptake.

Binding, Competitive↗
PubMed1985

Imipramine and desipramine disposition in the elderly.

Forty-six healthy male and female volunteers aged 21 to 88 received single 12.5-mg i.v. doses of imipramine, and 35 of these people received single 50-mg p.o. imipramine doses on a different occasion. Thirty-five similar volunteers received single 50-mg p.o. desipramine doses. Among these subjects 25 participated in studies of both imipramine and desipramine. Kinetic variables for the respective drugs were determined from multiple plasma drug concentrations from samples obtained during 96 hr after the dosage. Imipramine half-life was markedly prolonged in elderly vs. young males (28.6 vs. 16.5 hr; P less than .001) and females (30.2 vs. 17.8 hr; P less than .01) due to decreased clearance (males: 567 vs. 945 ml/min, P less than .01; females: 599 vs. 975 ml/min, P less than .005) with no change in volume of distribution. After p.o. imipramine doses time to peak imipramine concentration was shorter in elderly females (2.1 vs. 4.8 hr; P less than .005) but no different in males. Peak concentration achieved was greater in the elderly of both sexes (males: 40.2 vs. 19.5 ng/ml, P less than .005; females: 44.7 vs. 10.4 ng/ml, P less than .01). Comparison of p.o. and i.v. imipramine doses indicated no difference in absolute bioavailability between the elderly and young of either sex. In contrast, after p.o. desipramine more limited age-related changes were noted. Desipramine half-life was slightly prolonged in elderly males (30.8 vs. 21.2 hr; P less than .05) apparently related to a nonsignificant decrease in p.o. clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1979

Mechanism of imipramine inhibition of platelet 5-hydroxytryptamine transport.

Plasma membrane vesicles isolated from porcine blood platelets take up approximately 8 to 15 pmol of [3H]imipramine per mg of membrane protein. This apparent binding requires Na+ in the external medium and is reversed by 5-hydroxytryptamine and fluoxetine. The apparent KD for imipramine uptake is 23 nM, which agrees well with the KI for competitive inhibition of 5-hydroxytryptamine transport by imipramine. In contrast to 5-hydroxytryptamine transport, imipramine uptake is not dependent on transmembrane Na+ and K+ gradients and is insensitive to ionophores such as nigericin and gramicidin which dissipate these gradients. Although 5-hydroxytryptamine rapidly and competitively displaces imipramine from membrane vesicles, imipramine does not cause 5-hydroxytryptamine efflux and inhibits 5-hydroxytryptamine exchange. These results are consistent with the proposal that imipramine binds to the substrate site of the 5-hydroxytryptamine transporter but cannot be transported.

Animals↗
PubMedDate not supplied

Influence of chronic cigarette smoke exposure on the uptake and efflux of imipramine in the isolated perfused rat lung.

The pulmonary uptake and efflux of imipramine was determined in lungs removed from cigarette smoke-exposed and nonexposed rats. Using an isolated perfused lung preparation, the lung was perfused for 220 sec with medium containing 2.5 X 10(-7) M imipramine, followed by a 28-min drug-free perfusion. There was no significant difference (p less than 0.05) between either the rate or the amount of imipramine accumulated in the smoke-exposed and nonexposed animals. During the drug-free perfusion, the previously accumulated imipramine was released from two distinct pools (E1 and E2). Calculation of the total amount of effluxable imipramine indicated that in the nonexposed animals approximately 30% of the amount taken up did not efflux at a measurable rate but formed a "noneffluxable" pool. In the smoke-exposed animals, however, all of the accumulated imipramine appeared to be effluxable. These data demonstrate that there may be components of cigarette smoke which are sequestered by lung tissue at the binding sites associated with the noneffluxable pool of imipramine. The presence in cigarette smoke of components possessing such high pulmonary affinity may be a factor in cigarette smoke-mediated lung damage; this possibility is discussed.

Animals↗
PubMed1983

Binding of [3H]Ro 11-2465. Possible identification of a subclass of [3H]imipramine binding sites.

Ro 11-2465 is a cyanide derivative of imipramine. In cerebral cortex homogenates, [3H] Ro 11-2465 displays a binding profile similar to that of [3H]imipramine. Agents compete with binding of [3H]Ro 11-2465 in an order of potency similar to their ability to block serotonin uptake, and raphe lesions greatly decrease the binding of [3H]Ro 11-2465. These observations suggest that the sites labeled by [3H]Ro 11-2465 are presynaptic. The binding of [3H]Ro 11-2465 is sodium ion-dependent, as are both the binding of [3H] imipramine and the serotonin uptake mechanism. In the presence of sodium ions, binding of [3H]Ro 11-2465 to brain tissue or platelets at 4 degrees is apparently irreversible. Binding is not displaced by high concentrations of the displacing agent desipramine or by repeated washing. However, by either removing sodium or increasing the assay temperature to 23 degrees, the ligand dissociates from the tissue. In tissue where [3H]Ro 11-2465 is irreversibly bound to receptor at 4 degrees, subsequent [3H]imipramine binding is decreased by about 50%. At temperatures greater than 23 degrees, [3H]Ro 11-2465 binding displays a temperature dependency similar to that of [3H]imipramine; that is, when temperatures are raised from 23 degrees to 30 degrees or 37 degrees there is no change in the Bmax, but the affinity of the ligand for the receptor is decreased. These data suggest that [3H]Ro 11-2465 binds to a discrete population of [3H]imipramine binding sites, comprising about one-half of the total [3H] imipramine binding sites.

Animals↗
PubMed1994

Long-term safety and clinical acceptability of venlafaxine and imipramine in outpatients with major depression.

The antidepressant efficacy and safety of venlafaxine was shown previously in 6-week, placebo-controlled trials. We evaluated the long-term safety and clinical acceptability of venlafaxine and imipramine in a double-blind, parallel-group, comparative study. Two hundred ninety depressed outpatients were treated with venlafaxine, and an additional 91 received imipramine for as long as clinically necessary, up to 1 year. The total daily dose of each drug could vary from 75 to 225 mg. The Clinical Global Impressions Scale and a therapeutic response rate that was based on Clinical Global Impressions Scale-Improvement and incorporated discontinuation information were used to evaluate efficacy. Safety determinations and patient subjective ratings were used to evaluate safety and clinical acceptability. During the study, the adverse events were generally mild to moderate and most subsided with continued treatment; the most frequent were nausea for venlafaxine and dry mouth for imipramine. The anticholinergic side effect burden was significantly higher in the imipramine group than in the venlafaxine group. Venlafaxine was judged significantly more acceptable than imipramine, on the basis of the subjective ratings by patients. Fewer venlafaxine-treated patients than imipramine-treated patients withdrew because of adverse events and unsatisfactory response. There was a consistent trend in the therapeutic response rates in favor of venlafaxine that reached statistical significance at months 2, 6, and 12. In this long-term study, patient acceptability was greater for venlafaxine than for imipramine, suggesting therapeutic advantages for venlafaxine in the long-term treatment of depression. Additional studies with other active comparators are underway to confirm and extend these encouraging results.

Adult↗