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PubMed1993

Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver.

The metabolism of imipramine by human liver microsomes was examined using a combination of five strategies. Human hepatic microsomes produced N-desmethylimipramine (84%), 2-hydroxyimipramine (10%), and 10-hydroxyimipramine (6%). Preincubation of human hepatocytes in culture with beta-naphthoflavone and macrolides exclusively induced the formation of desmethylimpramine (552%, p < 0.05, and 234%, p < 0.003, respectively). Correlations were obtained between rates of imipramine demethylation and cytochrome P-450 (P-450) 1A2 (r = 0.88, p < 0.001) and P-450 3A (r = 0.80, p < 0.02) concentrations in human liver microsomal preparations from 13 different subjects. Anti-P-450 1A2 and anti-P-450 3A antibodies selectively inhibited N-demethylation (80% and 60%, respectively). N-Demethylation was completely inhibited when anti-1A2 and anti-3A were added simultaneously. Kinetic studies with human microsomes confirm the contribution of two different enzymes in the N-demethylation. The Km of 1A2 was similar to the high affinity Km in human liver microsomes, whereas the Km of 3A was similar to the low affinity Km in human liver microsomes. P-450 1A2 was apparently more efficient than 3A4 (lower Km and higher Vmax) but was expressed in much lower concentration. Human P-450s 1A2 and 3A4 expressed in yeast efficiently produced desmethylimipramine. These results suggest that P-450 1A2 and P-450 3A4 are the major enzymes involved in imipramine N-demethylation in human hepatic microsomes. Similar experiments were conducted using P-450 2D6, and they confirmed that P-450 2D6 catalyzes imipramine 2-hydroxylation. Interindividual variations in 3A4 hepatic content may explain the large variations in imipramine blood levels observed after uniform dosages and thus may explain the variations in clinical efficacy. Caution might be advised in the clinical use of tricyclic antidepressants when drugs are also administered that induce or inhibit P-450s 3A4 and 1A2.

Adult↗
PubMed1996

Imipramine distribution among red blood cells, plasma and brain tissue.

The relations between the concentrations of a drug in the blood (plasma, haemoglobin, red blood cells (RBCs), RBC membranes) and in the brain tissue (homogenate, membranes, cytosol) were investigated during chronic administration of imipramine. Radioimmunoassay was employed to measure the antidepressant concentrations. The concentrations were measured and analysed in 40 rats receiving various doses of imipramine. The concentration of total imipramine (imipramine + desipramine) in erythrocyte membranes (ghosts) amounted to 79.4 +/- 4.6% (mean +/- S.E.M., N = 40) of those measured in intact RBCs. Marked accumulation of the drug in the brain tissue, especially in brain cell membranes, was confirmed. The concentrations in brain tissue homogenate was found to be 14.8 times higher than that in RBCs. Values in brain membranes were 10.9 times higher than that in blood element membranes. There is a significant association between the concentrations measured in brain homogenate, the blood plasma and RBC membranes. Blood concentrations can be used to estimate imipramine concentrations in the brain.

Animals↗
PubMed1996

A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients.

Antidepressant effects of mirtazapine and imipramine were compared in a randomized, double blind, fixed blood-levels study with in-patients in a single centre. Patients with a DSM-III-R diagnosis of major depression and a Hamilton (17-item) score of > or = 18 were selected. After a drug-free and a placebo-washout period of 7 days in total, 107 patients still fulfilling the HRSD criterion of > or = 18, started on active treatment. The dose was adjusted to a predefined fixed blood level to avoid suboptimal dosing of imipramine. Concomitant psychotropic medication was administered only in a few cases because of intolerable anxiety or intolerable psychotic symptoms. Eight patients dropped out and two were excluded from analyses because of non-compliance; 97 completed the study. According to the main response criterion (50% or more reduction on the HRSD score) 11/51 (21.6%) patients responded on mirtazapine and 23/46 (50%) on imipramine after 4 weeks' treatment on the predefined blood level. Such a dramatic difference in efficacy between antidepressants has not often been reported before. The selection of (severely ill) in-patients, including those with suicidal or psychotic features, may have significance in this respect. Optimization of treatment with the reference drug imipramine through blood level control, exclusion of non-compliance for both drugs, exclusion of most concomitant medication and a low drop-out rate may also have contributed. It is concluded that imipramine is superior to mirtazapine in the patient population studied.

Adult↗
PubMedDate not supplied

Desmopressin and imipramine in the management of nocturnal enuresis: a multicentre study.

The efficacy and safety of desmopressin (Minirin/DDAVP) treatment compared with imipramine were investigated in a multicentre, open, cross-over design in 57 patients, aged 6-15 years, affected by nocturnal enuresis to establish the best therapeutic approach to this condition. After a two-weeks observation and control period, patients were randomised to one of two groups: intranasal administration of desmopressin, 30 micrograms/day for three weeks, followed by imipramine, 0.9 mg/kg for a further three weeks, or imipramine 0.9 mg/kg for three weeks, followed by desmopressin, 30 micrograms/day for a further three weeks. Following treatment, all patients were observed for a further two weeks. Administration of either treatment protocol resulted in a statistically significant decline in the number of enuretic episodes per week compared to the control. The greater antidiuretic effect observed in the group receiving imipramine followed by desmopressin suggests the two compounds have different profiles. Also, when the treatment period was compared with the follow-up, the antidiuretic effect had a longer duration in the group initially given imipramine. No further improvement was seen when desmopressin was administered first, with a mild worsening of the effect sometimes occurring, suggesting a different carry-over effect between the two treatments. This suggests that desmopressin offers a better approach to the management of nocturnal enuresis.

Adolescent↗
PubMedDate not supplied

Possible interaction between imipramine and butalbital.

A 44-year-old woman was admitted to the psychiatric unit for exacerbation of her depressive disorder. Blood concentrations of her antidepressant, imipramine, were within normal range and consistent with past concentrations. Her medical history was significant for a chronic headache disorder for which she was given a prescription containing butalbital on admission. The patient's depressive disorder was quickly controlled but relapsed 2 weeks later. Concentrations of imipramine showed a decrease of approximately 50%. Imipramine is metabolized in the liver by the cytochrome P-450 (CYP 1A2) system, and barbiturates are known inducers of this enzyme subset. To our knowledge, an interaction specifically between butalbital and imipramine has not been documented; however, these drugs are extensively prescribed and occasions may arise where they are given concurrently. We recommend repeat measurement of imipramine concentrations 1 week after the start of any butalbital-containing product or barbiturate, and dosage adjustments based on the results and on the patient's response to the change.

Adult↗
PubMed1976

Imipramine enhancement of pentobarbital toxicity in rats.

The toxicity of pentobarbital was examined in male Wistar rats pretreated with a non-toxic dose of imipramine (10 mg/kg, po). Pentobarbital (70 mg/kg, ip) lethality was enhanced up to 6 hr after imipramine administration, and pentobarbital (45 mg/kg, ip) sleeping time was prolonged up to 12 hr after imipramine. Physiological measurements showed that imipramine pretreatment 2 hr prior to pentobarbital (70 mg/kg, ip) enhanced barbiturate depression in mean blood pressure, oxygen consumption and respiration rate, but not in heart rate or back skin temperature. Analysis of brain radioactivity after [14C] pentobarbital indicated that these effects of imipramine were not solely the result of inhibition of liver metabolism.

Animals↗
PubMed1997

Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol.

The nonspecific, noncovalent binding of three drugs, imipramine, warfarin, and propranolol, to pooled human and animal liver microsomes has been determined using equilibrium dialysis in conditions where no cofactor (NADPH) was included in the incubation. The binding of warfarin was dependent upon both protein and drug concentration, whereas the binding of propranolol and imipramine was also dependent upon protein concentration but generally independent of drug concentration. At a microsomal protein concentration of 1.0 mg/ml and a warfarin concentration of 10 microM, the free fraction (fu(mic)) was 0.85. The corresponding values for propranolol and imipramine were 0.41 and 0.16, respectively. Thus, although all three drugs exhibit high binding in plasma (fu<0.1) the acidic drug warfarin differs from the basic drugs propranolol and imipramine in the extent to which each binds to microsomal protein. The binding of all three drugs to liver microsomes obtained from commonly studied animal species (rat, dog, and monkey) was almost identical to that observed in human. Additionally, the binding of warfarin and propranolol to microsomes obtained from insect cells used in baculovirus cytochrome P450 expression systems was similar to that exhibited in liver microsomes, when equal protein concentrations were compared. The enzyme kinetics of propranolol, imipramine, and warfarin oxidative metabolism were determined in pooled human liver microsomes, and the intrinsic clearance values obtained were used in scaling up to project human in vivo clearance. The values obtained by incorporating microsomal binding were compared with those in which this factor is ignored. The findings suggest that the parameter fu(mic) is important to obtain when attempting to relate in vitro intrinsic clearance to in vivo clearance. Also, this value is important to consider when comparing substrates with respect to enzyme specificity, since measured apparent KM values should be converted to true "free KM" values by correcting for the free fraction in the in vitro incubation. Furthermore, the extent of nonspecific binding to microsomes is likely an important parameter to consider when attempting to relate Ki values measured in vitro to observations of drug-drug interactions (or the lack thereof) in vivo.

Animals↗
PubMed1984

Temperature-sensitive conformational changes in [3H]imipramine binding sites and the involvement of sulphur-containing bonds.

Recently, a reversible, temperature-sensitive conformational change has been observed which alters [3H]imipramine binding parameters. I now report that the conformational change probably occurs within the binding site protein and is not due to allosteric interactions or altered ligand kinetics. Evidence comes from the identification of sulphur-containing bonds in the binding site molecule which are differentially exposed at different incubation temperatures. Binding of [3H]imipramine to outdated human platelets is maximal at 4 degrees C; when the incubation temperature is raised to 23 degrees C, a loss of affinity is observed. N-Ethylmaleimide, an alkylator of sulphydryl groups, could completely inhibit the binding at both temperatures but did so much faster at 23 degrees C than at 4 degrees C. Dithioerythritol (DTE) and beta-mercaptoethanol reduce disulphide bonds and were found to enhance [3H]imipramine binding. Again, these reagents were more potent at 23 degrees C than at 4 degrees C. None of these reagents caused these effects by interacting with the ligand. Simultaneous preincubation with excess fluoxetine could prevent the action of DTE on specific [3H]imipramine binding. It is concluded that sulphur-containing bonds are close to, or located at the [3H]imipramine binding site, and their conformation is sensitive to changing temperatures.

Blood Platelets↗
PubMed1980

Treatment of agoraphobia with group exposure in vivo and imipramine.

Seventy-six white agoraphobic women, 21 to 45 years old, were treated with combined group exposure in vivo and imipramine or placebo in a randomized double-blind study. A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement. However, imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement: primary phobia, spontaneous panic, and global improvement. There was a negative correlation between depression and outcome; ie, the more depressed patients fared worse on several outcome measures than those who were less depressed. A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment, but no significant difference between the two groups at the completion of therapy.

Adult↗
PubMed1981

Prophylactic lithium carbonate with and without imipramine for bipolar 1 patients. A double-blind study.

The efficacy of lithium carbonate plus imipramine hydrochloride vs lithium carbonate plus placebo in preventing relapse was assessed in a prospective, random-assignment double-blind study of 75 bipolar 1 patients. Outcome measures included type of relapse, time until relapse, and subsequent illness course. Infrequent depression relapse in either treatment group precluded any demonstration of an advantage of adding imipramine to a lithium carbonate regimen. There was little evidence that the combination of lithium carbonate and imipramine caused adverse reactions. However, interactions between type of most recent episode, treatment condition, sex, and type of relapse showed that women and mania-prone patients treated with imipramine had an increased risk of mania. Life table analysis showed that the overall probability of remaining well was the same for both treatment groups and that two thirds of all relapses occurred in the first six months.

Actuarial Analysis↗
PubMed1981

Depressed patients have decreased binding of tritiated imipramine to platelet serotonin "transporter".

The high-affinity tritiated (3H) imipramine binding sites are functionally (and perhaps structurally) associated with the presynaptic neuronal and platelet uptake sites for serotonin. Since there is an excellent correlation between the relative potencies of a series of antidepressants in displacing 3H-imipramine from binding sites in human brain and platelet, we have examined the binding of 3H-imipramine to platelets from 14 depressed patients and 28 age- and sex-matched controls. A highly significant decrease in the number of 3H-imipramine binding sites, with no significant change in the apparent affinity constants, was observed in platelets from the depressed patients compared with the controls. These results, coupled with previous studies showing a significant decrease in the maximal uptake of serotonin in platelets from depressed patients, suggest that an inherited or acquired deficiency of the serotonin transport protein or proteins may be involved in the pathogenesis of depression.

Adult↗
PubMed1982

Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison.

Twenty-seven patients with recurrent unipolar depression and 22 with bipolar II illness in remission for at least six months were randomly assigned on a double-blind basis to treatment regimens using lithium carbonate, imipramine hydrochloride, lithium carbonate plus imipramine, or placebo. Lithium carbonate was found to help prevent depressive relapse among patients with unipolar disease, and relapse of any type among those with bipolar II disease. No effect or interaction of imipramine was found in either group. These results add to a growing body of data that suggest the usefulness of lithium carbonate in the prophylaxis of unipolar depressive illness. The relative usefulness of lithium carbonate and imipramine requires further study.

Adolescent↗
PubMed1983

Treatment of phobias. I. Comparison of imipramine hydrochloride and placebo.

In a controlled-outcome study of phobias, 218 adult phobic patients (147 women and 71 men) received a course of 26 weekly treatment sessions that consisted of behavior therapy (BT) and imipramine hydrochloride, BT and placebo, or supportive psychotherapy and imipramine. The BT consisted of systematic desentization using fantasy and assertiveness training. Patients were classified as agoraphobic, mixed phobic, or simple phobic. Although the conditions of most patients in each group showed moderate to marked improvement, the effects of imipramine were significantly superior to those of placebo in patients with spontaneous panic attacks, ie, patients with agoraphobia or mixed phobia. In patients with simple phobia, who do not experience spontaneous panic, there was not a significant difference between imipramine and placebo. This study clearly distinguished those phobic patients who experienced spontaneous panic from those who did not in terms of pharmacologic benefits.

Adult↗
PubMed1986

Imipramine and chlordiazepoxide in depressive and anxiety disorders. I. Efficacy in depressed outpatients.

We randomly assigned 425 outpatients, independently classified as primarily depressed by two trained psychiatrists, to double-blind treatment with Imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo. Those patients who remained at least moderately depressed (following a two-week placebo washout period) were treated for an additional eight weeks. An endpoint analysis of 387 patients who completed two or more weeks of medication disclosed early therapeutic advantages of chlordiazepoxide. By week 4 of treatment, however, imipramine produced more improvement than did placebo and chlordiazepoxide. By six and eight weeks a general, marked therapeutic advantage was found for imipramine relative to placebo and to chlordiazepoxide on measures of depression, anxiety, anger-hostility, interpersonal sensitivity, and global improvement. Chlordiazepoxide-treated patients generally did significantly better on sleep difficulty but significantly worse on anger-hostility and interpersonal sensitivity than did imipramine- or placebo-treated patients.

Adult↗
PubMed1986

Imipramine and chlordiazepoxide in depressive and anxiety disorders. II. Efficacy in anxious outpatients.

A double-blind, placebo-controlled comparison at three collaborating university sites included 242 patients diagnosed as having anxiety disorders. A two-week placebo washout period preceded random assignment to eight weeks of imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo treatment. Antianxiety effects of imipramine were superior to those of the other two agents by the second treatment week; these effects became more clearly significant thereafter and were independent of degree of both baseline depression and anxiety. Excluding patients with possible panic-phobic syndromes from the analyses removed most significant antiphobic and antidepressant effects of imipramine but left intact imipramine's significantly superior antianxiety effects.

Adult↗
PubMed1987

Alprazolam, diazepam, imipramine, and placebo in outpatients with major depression.

Two hundred forty-one outpatients with a DSM-III diagnosis of major depressive disorder participated in a six-week double-blind therapeutic trial of alprazolam, diazepam, imipramine hydrochloride, and placebo. Side effects were given as a major reason for attrition by patients taking the three active compounds and ineffectiveness was the reason given by patients taking placebo. Imipramine-treated patients reported the most and placebo patients the least number of adverse effects. Imipramine and alprazolam, but not diazepam, produced significantly more improvement in depressed symptomatology than did placebo. Mean diazepam scores frequently assumed an intermediate position between those of imipramine or alprazolam and placebo. These treatment differences were found to be independent of initial severity levels of anxiety and depression.

Adult↗
PubMed1989

Phenelzine and imipramine in mood reactive depressives. Further delineation of the syndrome of atypical depression.

Sixty patients who met Research Diagnostic Criteria for major, intermittent, or minor depressive disorder and had reactive mood without atypical symptoms were treated with imipramine hydrochloride, phenelzine sulfate, or a placebo. These patients, referred to as simple mood reactive depressives, were contrasted with previously published data from 180 atypical depressives. Atypical depressives had the presence of at least one vegetative atypical sign (hypersomnia, hyperphagia, leaden feeling, or rejection sensitivity) but were otherwise indistinguishable from simple mood reactive depressives. In contrast to the atypical depressives for whom phenelzine was effective and imipramine was relatively ineffective, both medications were equivalently good in simple mood reactive depressives. Since all groups did poorly when given a placebo and well when given phenelzine, the salient feature of atypical symptoms may be that they predict poor response to imipramine. Since the difference between imipramine and placebo depends on the diagnostic group, pharmacologic dissection suggests that atypical symptoms in patients with nonautonomous mood may delineate a qualitatively distinct subgroup.

Adult↗
PubMed1993

Antidepressants for the treatment of generalized anxiety disorder. A placebo-controlled comparison of imipramine, trazodone, and diazepam.

OBJECTIVE: The current study examines whether antidepressants, contrary to current thinking, are safe and effective treatments for generalized anxiety disorder (GAD) not complicated by depression or panic disorder. DESIGN: Randomized, double-blind, placebo-controlled, flexible-dose, 8-week treatment study comparing imipramine hydrochloride (mean maximum daily dose, 143 mg), trazodone hydrochloride (255 mg), and diazepam (26 mg). PATIENTS: Two hundred thirty patients with a DSM-III diagnosis of GAD in whom major depression and panic disorder has been excluded, and who had a Hamilton Anxiety Scale total score of at least 18. SETTING: Seventy-five percent of patients were treated in family practice settings in the community, with the remainder treated in psychiatric practices, either academic or private. RESULTS: Patients treated with diazepam showed the most improvement in anxiety ratings during the first 2 weeks of treatment, with somatic symptoms being most responsive. From week 3 through week 8 trazodone achieved comparable, and imipramine somewhat better, anxiolytic efficacy when compared with diazepam, with psychic symptoms of tension, apprehension, and worry being more responsive to the antidepressants. Among completers, moderate to marked improvement was reported by 73% of patients treated with imipramine, 69% of patients treated with trazodone, 66% of patients treated with diazepam, but only 47% of patients treated with placebo. Overall, patients treated with antidepressants reported a higher rate of adverse effects than diazepam-treated patients, but attention rates were the same across all treatments. CONCLUSIONS: The results of the study need replication, but suggest a potentially important role for antidepressants, particularly imipramine, in patients suffering from GAD.

Adult↗