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Chronic depression: response to placebo, imipramine, and phenelzine.

We reanalyzed data from a larger, previously published study in order to directly address whether very chronically depressed patients could benefit from antidepressant medications. This study entered 598 depressed patients into a study randomizing patients to 6 weeks of double-blind treatment with imipramine, phenelzine, or placebo. Patients were assessed for chronicity on a four-point scale from "mostly well" to "virtually always depressed." The current analyses include only the 153 study completers who were rated as "virtually always depressed." In these patients, imipramine was effective for significantly more patients than was placebo (22 [46%] of 48 responding to imipramine vs. 9 [17%] of 52 responding to placebo; chi 2 = 9.50; p = 0.002), whereas phenelzine was significantly more effective than imipramine (37 [70%] of 53 responding to phenelzine; chi 2 = 5.96; p = .015). Patients with mild depression, early onset, or histories of panic attacks did not have substantially different outcomes than patients without these characteristics. These findings suggest that some chronically depressed patients may be good candidates for treatment with antidepressant medication. Because the majority (80%) of the sample met Columbia criteria for definite or probable atypical depression, too few chronic depressives were available to evaluate separately antidepressant efficacy in chronically depressed outpatients who did not have atypical depression. Hence, these results may be applicable only to patients with atypical depression.

Adult↗

Ritanserin, imipramine, and placebo in the treatment of dysthymic disorder.

Fifty outpatients with dysthymic disorder (DSM-III) were divided by double-blind randomized assignment into three groups given ritanserin, imipramine, and placebo, respectively. The trial was of 7 weeks' duration; by week 6, imipramine was clearly superior to placebo, whereas by week 7, both drugs caused significantly more improvement than the placebo. Although imipramine had slightly greater efficacy than ritanserin, it also had significantly more side effects. This was particularly evident in the higher dropout rate with imipramine. The efficacy and side effect profile of ritanserin makes it well tolerated and acceptable with dysthymic patients who, although they do not respond as quickly as patients with major depressive disorder, do show significant improvement, given sufficient time.

Adult↗

Fluvoxamine-induced alterations in plasma concentrations of imipramine and desipramine in depressed patients.

The effect of fluvoxamine maleate, 100 mg/day for 10 days, on plasma concentrations of tricyclic antidepressants was studied in 15 depressed patients on maintenance therapy with imipramine (7 pts.) or desipramine (8 pts.). In the subgroup treated with imipramine, plasma levels of imipramine increased significantly (p < 0.001) during fluvoxamine coadministration, while levels of desipramine were not modified. Addition of fluvoxamine to patients on a stable desipramine dosage regimen resulted in a slight, but statistically not significant, increase in desipramine plasma concentrations. These results suggest that fluvoxamine is a potent inhibitor of imipramine demethylation, while it has a weak effect on the hydroxylation of desipramine.

Adult↗

[Randomized double-blind comparative study of the efficacy and tolerance of medifoxamine and imipramine in depressed patients].

Medifoxamine (Clédial TM), a non tricyclic non MAOI antidepressant drug with a dopaminergic and serotoninergic mechanism of action, was compared to imipramine in a multicenter double blind trial. Patients suffering from DSM III-R major depression (without psychotic features), with a minimum inclusion score of 25 at the MADRS after an initial 7-day wash-out period, were randomly assigned to a 4-week treatment by either imipramine or medifoxamine, with flexible doses of at least 100 mg after 2 weeks of treatment. No associated treatment was permitted except for lorazepam 2 to 5 mg per day. Ninety eight patients were recruited by 20 centers throughout France. Eighty four terminated the 4-week protocol. Early terminations were due to serious adverse events (3), death on imipramine (1), protocol violation (1), refusal to continue (1), loss to follow up (1). The 2 groups of patients were comparable on inclusion. In the medifoxamine group (receiving a daily dose of 194 mg at day 28) the percentage of improvement in MADRS scores, the number of patients with a MADRS improvement of a least 50% and a final MADRS score inferior to 8, were not significantly different from the imipramine group (daily dose: 161 mg at day 28). No more difference appeared when several clinical variables were analyzed, in particular the DSM III-R melancholic, the Newcastle endogenous subtypes and the in or out patient status. The two treatment groups were also comparable on other scales (HDRS, HARS assessing anxiety, CGI).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Inhibition and induction of cytochrome P450 isozymes after repetitive administration of imipramine in rats.

Repetitive oral administration of imipramine (100 mg/kg/day for 5 days) caused a decrease in rat liver microsomal debrisoquine 4-hydroxylase activity, a characteristic reaction catalyzed by cytochrome P450 (CYP) 2D1. Other CYP2D-dependent reactions (such as bunitrolol 4-hydroxylation, lidocaine 3-hydroxylation, and propranolol 4-, 5- and 7-hydroxylations) were also impaired by the treatment, but not those catalyzed by other CYP isozymes. Imipramine pretreatment did not change the immunochemically determined content of the CYP2D protein, suggesting that CYP2D is inactivated. Imipramine pretreatment also resulted in an increase in total CYP content and in formation of a ferrous CYP metabolic intermediate (MI)-complex absorbing at 454 nm. Although the total CYP content was increased by the treatment of these microsomes with ferricyanide to dissociate the MI-complex, the CYP2D-dependent activities were not restored, suggesting that the MI-complex was not the primary cause of CYP2D inhibition. This pretreatment regimen caused marked increases in immunochemically determined levels of CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A2, and in the activities of 2 alpha-, 2 beta-, 6 beta-, 7 alpha-, 16 alpha-, and 16 beta-hydroxylation and 17-oxidation of testosterone. These results indicate that imipramine has two actions on the liver CYP system (i.e. as an inhibitor of the CYP2D enzyme and as a phenobarbital-type inducer).

Adrenergic beta-Antagonists↗

[Effect of imipramine hydrochloride on urinary function and serum parameters in enuretic children: preliminary study].

We still do not know whether Imipramine works exactly as an antidiuretic. The aim of this study was to investigate any existing urinary or serum factor differences between 9 children with primary nocturnal enuresis and six age and sex matched controls and to see if therapy with Imipramine could modify these parameters. All subjects underwent an evaluation of daily and nightly urinary volume, daily fluid intake, morning plasma and urine osmolality, plasma aldosterone, electrolytes, blood urea nitrogen and plasma glucose. The results, using a one-way ANOVA, would suggest the following: 1) enuretic children have a higher 24 urinary volume with a reduced osmolality compared to controls; 2) Aldosterone does not seem to be involved in the pathogenesis of enuresis; 3) Imipramine HCL therapy does reduce the volume of urine lost in diapers, and its efficiency can be documented objectively; 4) Imipramine HCL's mechanism appears to be related to an increased renal water resorption.

Analysis of Variance↗

Altered disposition and antidepressant activity of imipramine in transgenic mice with elevated alpha-1-acid glycoprotein.

Imipramine is a tricyclic antidepressant known to be bound in the serum primarily by alpha-1-acid glycoprotein. The present study examined the effect of changes in serum alpha-1-acid glycoprotein levels on the pharmacokinetics and antidepressant activity of the drug by utilizing a novel set of transgenic mice in which the steady-state level of alpha-1-acid glycoprotein is significantly elevated over normal. The pharmacokinetic disposition was characterized after i.v. and i.p. injections in transgenic and control mice. In transgenic mice, there were significant decreases in the serum unbound fraction (0.62+/- 0.38 vs.2.48 +/- 0.43%), Vd (9.0 +/- 2.5 vs. 22.4 +/- 3.2 liters/kg), T1/2 (35.0 +/- 7.6 vs. 65.3 +/- 7.6 min) and fraction of dose excreted unchanged in urine (0.14 +/- 0.07 vs. 0.70 +/- 0.20%) with no significant alterations in systemic clearance (204.7 +/- 56.1 vs. 292.8 +/- 58.4 ml/min/kg) compared to control values. The antidepressant activity of imipramine was measured by a swimming-immobility test 30 min after either imipramine (30 mg/kg i.p.) or saline treatment. After saline treatment, there were no significant differences in the duration of swimming despair between transgenic (183 +/- 24 sec) and control (175 +/- 12 sec) mice. Imipramine treatment resulted in reductions in the duration of immobility in both transgenic (130 +/- 21 sec) and control (54 +/- 33 sec) mice. The extent of reduction was significantly less in transgenic animals than in control animals. These alterations in the antidepressant action appeared to correlate with the unbound drug concentration but not with the total drug concentration.

Animals↗

A double-blind placebo-controlled trial comparing fluvoxamine and imipramine in the treatment of panic disorder with or without agoraphobia.

This study compared the efficacy, tolerability, and safety of fluvoxamine, imipramine, and placebo in the treatment of panic disorder with or without agoraphobia. Fifty-four outpatients participated in the randomized, double-blind trial as part of a multicenter trial. After meeting inclusion criteria and completing screening requirements (e.g., laboratory testing, electrocardiogram, physical examination), patients were entered in a single-blind placebo washout phase. They were then randomized to either fluvoxamine, imipramine, or placebo. Measurements completed at each visit included the number and severity of panic attacks per week, the Sheehan Panic and Anticipatory Anxiety Scale, and the Clinical Global Impressions, and others. Results show that fluvoxamine is more effective than placebo and as effective as imipramine in reducing spontaneous panic attacks in moderate to severe panic disorder. However, starting doses of fluvoxamine and imipramine should be low to minimize untoward side effects (such as insomnia and agitation) and maintain compliance.

Adult↗

A double-blind comparison of gepirone extended release, imipramine, and placebo in the treatment of outpatient major depression.

We report the results from one site of a two-site, double-blind, placebo-controlled comparison study of gepirone extended release (ER) and imipramine in the management of major depression. In the study, 123 subjects with DSM-III-R major depression were randomized to 8 weeks of treatment with gepirone ER (10-60 mg/day), imipramine (50-300 mg/day), or placebo. According to last observation carried forward (LOCF) analyses of 120 intent-to-treat subjects, both gepirone ER and imipramine were superior to placebo at Weeks 6 and 8 on the Hamilton Rating Scale for Depression 17- and 28-item (HAM-D-17 and HAM-D-28) instruments, the Clinical Global Impressions (CGI) Severity of illness scale, and the total Bech Six-Item Core Depression Cluster score. Gepirone ER was better tolerated than imipramine when judged by dropout rates for adverse events.

Adult↗

A preliminary study on the efficacy of sertraline and imipramine on anger attacks in atypical depression and dysthymia.

There is clinical and biological evidence suggesting that patients with anger attacks, sudden spells of anger accompanied by intense autonomic activation, may represent a distinct psychopathological subgroup of patients with depressive disorders. We compared the prevalence of anger attacks in 168 outpatients with atypical depression or primary dysthymia with 38 normal subjects and tested the effect of treatment on anger attacks in a double-blind, placebo-controlled trial of sertraline versus imipramine. Patients were randomly assigned to sertraline (n = 56), imipramine (n = 52), or placebo (n = 60) and were administered the Anger Attacks Questionnaire before and after treatment. Depressed outpatients were significantly more likely to report anger attacks than controls. Anger attacks ceased in 53 percent of the patients receiving sertraline, 57 percent of those receiving imipramine, and 37 percent of those in the placebo group. Our findings support previous studies indicating that anger attacks are more prevalent among depressed outpatients than normals. Our results also suggest that sertraline and imipramine may be more effective than placebo in reducing the number of anger attacks following treatment although the differences were not statistically significant. Larger studies are needed to confirm our findings.

1-Naphthylamine↗

Imipramine induces alterations in proenkephalin and prodynorphin mRNAs level in the nucleus accumbens and striatum in the rat.

Endogenous opioids have been implicated in the mechanism of action of antidepressant drugs. In this study, we evaluated effects of single and repeated imipramine administration on proenkephalin and prodynorphin gene expression in the rat nucleus accumbens and striatum. In situ hybridization study showed that single imipramine injection (10 mg/kg, i.p.) decreased the level of proenkephalin (by ca. 20%) and prodynorphin (by ca. 25%) mRNA to the same extent in both structures. Repeated imipramine administration (10 mg/kg i.p. twice daily for 10 days) had no effect on proenkephalin mRNA level, whereas the prodynorphin gene expression was regulated differently. At 3 h after the last dose of imipramine the prodynorphin mRNA level was decreased (by ca. 25%) in the striatum, but not in the nucleus accumbens, whereas at 24 h an up-regulation (by ca. 27%) of prodynorphin mRNA level could be observed in the nucleus accumbens only. In the light of involvement of opioids in mood regulation, these adaptive changes may participate in neurochemical mechanisms of antidepressant therapy.

Animals↗

Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain.

Imipramine hydrochloride (CAS 113-52-0) is a widely used antidepressant and can interact with opioid receptors. However, complete information concerning possible regional alterations in mu-opioid receptor expression in the rat forebrain after chronic treatment with this substance is still lacking. This being the case, analysis of mu-opioid receptor immunostaining in several regions of the rat brain after imipramine administration in vivo was made, and an increase in the density of cells expressing mu-opioid receptors in the caudatus-putamen, the dentate gyrus and the frontal, parietal and piriform cortices after chronic imipramine treatment, with respect to controls, was found. These data suggest that mu-opioid receptor expression in the rat forebrain is altered by in vivo chronic imipramine treatment.

Animals↗

Gas-chromatographic analysis for therapeutic concentration of imipramine and disipramine in plasma, with use of a nitrogen detector.

We describe a method for the simultaneous gas-chromatographic analysis of imipramine and desipramine (the active N-desmethyl metabolite) at therapeutic concentrations in human plasma, with use of a nitrogen detector. Imipramine is measured as the unchanged base and desipramine as its N-tribluoroacetyl derivative. Promazine is the internal standard. The lower limit of sensitivity is 5 mug/liter for each drug, and the within-day coefficients of variation for the determination of imipramine and desipramine, respectively, are 6.0% and 3.3%. We measured concentrations of these drugs both in patients receiving therapeutic doses of imipramine and in those who had ingested an overdose.

Chromatography, Gas↗

Specific high affinity [3H]imipramine binding sites in rat lung are associated with a non-neuronal uptake site for serotonin.

[3H]Imipramine binds to rat lung membranes. The binding is saturable, of high affinity and sodium-dependent. Drug displacement studies indicate that the binding site in rat lung is similar to that already described in the brain cortex. Tricyclic antidepressants inhibited [3H]imipramine binding in the lung in the low nanomolar range and through a competitive interaction. Serotonin and non-tricyclic serotonin uptake blockers inhibited [3H]imipramine binding in lung in a complex manner. Our results support the view that [3H]imipramine binding and the serotonin recognition site of the transporter are related but not identical.

Animals↗

Multiple [3H]imipramine binding sites in brains of male and female Fawn-Hooded and Long-Evans rats.

Comparisons of high- and low-affinity [3H]imipramine binding to whole brain homogenates from adult male and female rats of the Fawn-Hooded and Long-Evans strains were performed. Most strikingly, no significant differences were observed between the two strains in any of the binding parameters, indicating that brain [3H]imipramine binding sites, which may be related to the serotonergic uptake process, appear normal in a strain of rats with serotonin platelet storage pool disease. However, a significant sex difference in high- but not low-affinity whole brain [3H]imipramine Bmax values was observed, with females of both strains having higher densities than males. The observed sex difference in densities of high-affinity [3H]imipramine binding sites necessitates further research into possible sex hormone interactions with this binding site and serotonergic transmitter systems.

Animals↗

Post-thaw motility and longevity of motility of imipramine-induced ejaculates of pony stallions.

Imipramine-induced ex copula ejaculates (11) and fractionated in copula ejaculates were collected from each of 5 pony stallions for freezing in 5-ml straws (6), using a modified Kenney glucose skim-milk extender (2). Initial post-thaw total and progressive motilities and daily post-thaw total and progressive motilities, as well as the number of days to reach 0 progressively motile spermatozoa, were also similar for the 2 methods of collection. The percentage of morphologically normal spermatozoa both before freezing and after thawing were also similar for in copula and ex copula ejaculates. Consistent with previous work (11), imipramine-induced ejaculates were of extremely high sperm concentration and low volume compared with those of in copula ejaculates. In this study, imipramine-induced ejaculates were of significantly higher concentration of sperm and lower volume than fractionated (first 2-3 jets) in copula ejaculates. These results suggest that imipramine-induced ejaculates may be suitable for cryopreservation. Breeding trials are necessary to evaluate actual fertility of semen.

Journal Article↗

Quantitative autoradiographic evidence for axonal transport of imipramine receptors in the central nervous system of the rat.

Interruption of the ascending serotonin axons of the medial forebrain bundle (MFB) in the rat brain produced a progressive time-dependent accumulation of imipramine receptors (labeled for autoradiography with [3H]imipramine). The largest accumulation of receptors occurred during the first 12 h at the caudal aspect of the lesion. An electrolytic lesion of the nucleus raphe dorsalis, administered 24 h prior to interruption of the medial forebrain bundle, markedly reduced the number of imipramine receptors on the caudal side of the lesion, while a significant accumulation was still evident on the rostral aspect. These results suggest that imipramine receptors are undergoing the process of orthograde axonal transport to terminals in the forebrain from the neuronal perikarya found in the nucleus raphe dorsalis. These receptors may also be undergoing retrograde transport back to their cell bodies of origin.

Animals↗

Antidepressant response to tricyclics and urinary MHPG in unipolar patients. Clinical response to imipramine or amitriptyline.

The urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) was measured in unipolar depressed patients before and during the fourth week of treatment with either imipramine hydrocloride or amitriptyline hydroxhloride. On the basis of strict rating criteria, 24 patients were selected as either unequivocal responders or nonresponders. In the imipramine group the mean pretreatment MHPG was significantly lower in the nine responders in the seven nonresponders; the converse was found with the amitriptyline patients. Of particular interest is that there was no overlap in individual values between the responders and nonresponders to either drug. Treatment with eigher imipramine or amitriptyline was associated with a significant decrease in MHPG excretion, which was independent of clinical response.

Adult↗