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PubMed1998

Imipramine inhibits soluble enkephalin-degrading aminopeptidase activity in vitro.

Considerable evidence has appeared recently connecting the mechanism of action of some antidepressant drugs with the inhibition of the enzymes responsible for enkephalin degradation. Imipramine in vitro inhibits the enkephalin-degrading aminopeptidase MII and interacts with the enzyme in a mixed competitive-noncompetitive manner. The present work shows that imipramine in vitro also inhibits reversibly soluble enkephalin-degrading aminopeptidase activity in rat brain. Kinetic analysis showed that this enzyme has two different binding sites for the drug, and that imipramine interacts with the enzyme in a mixed noncompetitive-acompetitive way.

Aminopeptidases↗
PubMed1993

Prospective study of the electrocardiographic effects of imipramine in children.

Because imipramine and desipramine have been implicated in sudden death in children, noninvasive electrophysiologic data were accumulated in 25 patients. Two children were excluded on the basis of resting electrocardiographic and Holter abnormalities. The remaining 23 patients received imipramine to a maximum dose of 5 mg/kg or a serum level of 150 to 250 ng/ml. Consistent but clinically insignificant resting electrocardiographic changes occurred during treatment. Ambulatory electrocardiographic monitoring may be useful when one is assessing the cardiovascular risks of imipramine therapy.

Adolescent↗
PubMedDate not supplied

CPT performance in major depressive disorder before and after treatment with imipramine or fluvoxamine.

Numerous neuropsychological studies have reported deficits in cognitive and attentional functioning in depressed patients. However, there are limited data available about unmedicated depressed patients and the effects of antidepressant treatment on attentional performance. In this study, a Continuous Performance Test (CPT) was employed to evaluate the attentional performance of depressed inpatients during a drugfree period (n = 52) in comparison to healthy control subjects (n = 73). After 4 weeks of double-blind treatment with imipramine (TCA) or fluvoxamine (SSRI) at adequate plasma levels the CPT performance was studied again. We found that the unmedicated patients had a significantly impaired performance on all CPT parameters (reaction time, omission errors and commission errors) in comparison to the controls. None of the CPT parameters correlated with the severity of the depression or the level of psychomotor retardation. However, the CPT performance in the patient group was significantly related to subjective mood state (depression, tension). Double-blind treatment with imipramine or fluvoxamine resulted in an improvement of the CPT performance. In the imipramine treatment group the mean reaction time decreased significantly, and after treatment with fluvoxamine a significant decrease of the mean reaction time and the number of omission errors was detected. Both antidepressants induced a significant improvement of clinical state, but we did not find a relationship between the altered CPT performance and the changes on the clinical scales. Future studies should investigate other mechanisms underlying the improved attentional performance after treatment.

Adult↗
PubMedDate not supplied

Differential effects of fluoxetine and imipramine on the phosphorylation of the transcription factor CREB and cell-viability.

It has been shown that antidepressants increase the expression of CREB (cAMP-response-element-binding-protein) and BDNF (brain derived neurotrophic factor) in vivo. Apparently inconsistent to these survival-promoting properties for many years antidepressants are known to induce apoptosis in various cell types in vitro. In the present study we evaluated if the antidepressants imipramine and fluoxetine are capable to influence the translational expression and phosphorylation of CREB (pCREB) in cells known to be apoptosis-inducible by antidepressants. We therefore used jurkat cells and quantified apoptosis via propidiumiodid-staining and FACS-analysis. CREB-expression and -phosphorylation was quantified via western blot. Both antidepressants induced apoptosis within 24 h. Fluoxetin starts to induce significant apoptosis at a concentration of 20 microM, whereas imipramine at 100 microM. At these concentrations both antidepressants also increased the phosphorylation of CREB within 6 h. But even in concentrations to low to induce apoptosis both antidepressants still increased CREB-phosphorylation. Treating cells with lowest concentrations only imipramine revealed an increase of CREB-phosphorylation after long-time treatment over 3 weeks. In all experiments overall CREB-expression remained unchanged. In conclusion our experiments indicate that antidepressants are capable to increase CREB-phosphorylation without induction of apoptosis depending on concentration and duration of treatment. We further assume that antidepressants induce CREB-phosphorylation via signal transduction pathways that are different from those inducing apoptosis.

Antidepressive Agents, Second-Generation↗
PubMed2001

Effect of ACTH on the imipramine- and desipramine-induced decrease in duration of immobility time as measured in a rat forced swimming test.

In a rat forced swimming test (FS), we examined the effect of repeated injections of ACTH (adrenocorticotropic hormone) for 14 days on the decreased duration of immobility time produced by imipramine and desipramine. Both imipramine (15 and 30 mg/kg, p.o.) and desipramine (15 and 30 mg/kg, p.o.) significantly decreased the duration of immobility time in the FS. On the other hand, ACTH (100 microg/kg, i.p.) alone did not affect the duration of immobility time in FS. When ACTH (100 microg/kg, i.p.) was injected for 14 days before the 15-min swim session, it counteracted the decreased duration of immobility time induced by both imipramine and desipramine. Thus, ACTH seems to play a key role in decreasing the duration of immobility time of antidepressants in this test.

Adrenocorticotropic Hormone↗
PubMed1997

Interaction mechanisms of imipramine and desipramine with enkephalin-degrading aminopeptidases in vitro.

In the last few years, considerable evidence has appeared concerning the importance of the opioid systems in the action mechanism of some antidepressant drugs. This action mechanism could be mediated through the inhibition of the enzymes responsible for enkephalin degradation. In this sense, imipramine treatment in vivo increases the enkephalin levels, and this effect is enhanced by inhibitors of enkephalin-degrading enzymes. The present work shows the effects in vitro of imipramine and its active metabolite desipramine on the activities of two membrane-bound enkephalin-degrading aminopeptidases present in rat brain. Imipramine and desipramine in vitro do not affect the aminopeptidase M activity, but they reversibly inhibits the aminoeptidase MII. The enzyme kinetic analysis shows that this enzyme molecule has two different binding sites for each drug, which exert a mixed type enzyme inhibition.

Aminopeptidases↗
PubMed2002

Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus.

Previous studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a subsensitivity of group I metabotropic glutamate receptors (mGluR) in hippocampus. In the present study effects of antidepressant treatment on the expression of mGluR1a and mGluR5a, belonging to the group I mGluR, were investigated in rat brain hippocampus using immunohistochemical and Western blot methods, respectively. Male Wistar rats were treated singly or chronically for 21 days with imipramine, 10 mg/kg, twice daily; with ECS (90 mA, 50 Hz, 0.5 s) every second day; or with haloperidol, 1.2 mg/kg, once daily. Appropriate controls were injected with saline. Rats were sacrificed 24 h after the last treatment and their hippocampi were taken out for analysis. It was found that the mGluR1a-immunoreactivity expression increased significantly in Ammon's horn (CA) regions after chronic ECS. The most pronounced effect was observed in the CA3. No significant effects were found after single treatment or after haloperidol. The expression of mGluR5a increased significantly after chronic imipramine in the CA1 and after chronic ECS in the CA3 region. The results obtained indicate an influence of antidepressant treatment on group I mGluR. This increase in the receptor protein level may be a compensatory mechanism developing after chronic treatment.

Animals↗
PubMed1999

The effect of prolonged imipramine and electroconvulsive shock treatment on calcium/calmodulin-dependent protein kinase II in the hippocampus of rat brain.

The phosphorylation of substrate proteins by protein kinases plays a key role in signal transduction and function of neurons. Protein kinases have been associated with several physiological and pathological states including depression. The aim of the present study was to investigate the effect of imipramine and electroconvulsive treatment (ECS), both clinically effective treatments of depression, on the activity of calcium/calmodulin dependent protein kinase II (CaM-KII) in the hippocampus. Our results indicate that repeated (but not acute) imipramine and ECS administration significantly decreased CaM-KII activity by 65 and 70%, respectively, in the soluble fractions from hippocampus. This decreased enzyme activity was accompanied by a proportional decrease (60-70%) of the amount of a-CaM-KII in the same fraction. A single and repeated administration of imipramine produced a significant increase in the activity of CaM-KII (50 and 337%, respectively) in the particulate fraction from hippocampus. Similarly, a single and repeated ECS produced an increase in the enzyme activity by 22 and 240%, respectively. The amount of a-CaM-KII in the particulate fraction was not significantly affected by repeated antidepressant administration. It is postulated that changes in CaM-KII activity following chronic antidepressant treatment might represent and important step in expression of its antidepressive action.

Animals↗
PubMedDate not supplied

Failure of neonatal clomipramine treatment to alter forced swim immobility: chronic treadmill or activity-wheel running and imipramine.

We examined whether chronic running on a treadmill or activity wheel would attenuate the increased swim immobility that has been reported after neonatal clomipramine (CLI) treatment. Male Sprague-Dawley pups (N = 60) were injected with the monoamine reuptake inhibitor clomipramine hydrochloride (40 mg/kg per day i.p.) from 8 to 21 days of age. Another group (N = 12) received saline vehicle. At age 4 weeks, the CLI pups were randomly assigned to experimental conditions: (1) sedentary; (2) 24-h access to an activity wheel; (3) sedentary that received the antidepressant drug imipramine hydrochloride (10 mg/kg twice daily) during the last 10 days of the experiment; (4) activity wheel + imipramine; (5) treadmill running (30 m/min for 1 h at 0 degrees incline, 6 days/week). At age 16 weeks, rats underwent the Porsolt swim test 48 h after the last imipramine injection and/or the last exercise session. The increase in swim immobility among CLI-treated rats was small (one quarter of SD) and not statistically significant (p>0.10). The results are not consistent with our previous finding of antidepressant-like effects of activity-wheel running based on brain noradrenergic adaptations and enhanced male copulatory performance after neonatal CLI treatment. The lack of change in swim performance after clomipramine questions the generalizability of the CLI model of depression and the validity of the forced swim test as a behavioral measure of depression when it is used after neonatal CLI injection or chronic activity-wheel running.

Adrenergic Uptake Inhibitors↗
PubMed2002

Effect of chronic treatment with milnacipran on sleep architecture in rats compared with paroxetine and imipramine.

A number of studies in humans and various other species have shown that chronic treatment with antidepressants, such as tricyclics or selective serotonin reuptake inhibitors (SSRIs), induces a decrease or suppression of rapid eye movement (REM) sleep. The effect of a new selective serotonin and noradrenaline reuptake inhibiting (SNRI) antidepressant, milnacipran, on REM sleep has been investigated and compared with that of the SSRI, paroxetine, and the tricyclic, imipramine. Rats injected with vehicle or milnacipran twice a day showed, over 24 h, a similar amount of REM sleep, number and duration of REM sleep episodes to control rats. In contrast, rats treated acutely with imipramine or paroxetine showed a statistically significant decrease in the total quantity of REM sleep. The number of REM sleep episodes was decreased while their duration was increased. A more detailed analysis showed further that the quantity of REM sleep was decreased for the first 4 h following the 9 a.m. injection but not the 7 p.m. injection for milnacipran, during the first 6 h for paroxetine and for the entire light-dark period for imipramine. For all drugs, the quantities of slow-wave sleep and waking over 24 h were not significantly different from control conditions and no rebound of REM sleep occurred during the day following withdrawal. Power spectrum analysis revealed no global changes in the different electroencephalogram (EEG) waves (delta, theta, gamma) between the control condition and the different treatments during waking, slow-wave sleep or REM sleep. Taken together our results indicate that the SNRI, milnacipran, at therapeutic doses, induces only minor disturbances of REM sleep compared with a SSRI and tricyclic antidepressant used. Possible mechanisms responsible for the difference of action on REM sleep of milnacipran are discussed.

Adrenergic Uptake Inhibitors↗
PubMed2002

Loss of the circadian variation of platelet [3H]imipramine binding in delusional compared with non-delusional endogenously depressed patients.

BACKGROUND: The circadian variations of the serotonin reuptake sites were studied in 16 patients meeting DSM-IV criteria for major depression with melancholia, either with (n=8) or without (n=8) psychotic symptomatology. METHOD: The [3H]imipramine binding sites were measured in platelet samples. RESULTS: While no statistically significant difference was found between the morning (09:00 h) and evening (21:00 h) [3H]imipramine B(max) values in the control group, both the non-delusional and delusional melancholic patients showed higher evening than morning B(max) values, which were only statistically significant in the former. When both diagnostic groups were compared, the delusional patients showed significantly lower [3H]imipramine binding values than the non-delusional patients both in the morning and evening samples. Within the non-delusional depressed patients, those individuals with mood circadian variation, assessed by the 18th item of the HDRS, showed significantly lower B(max) values than those without mood variation. Lowest morning and evening B(max) values were noted in the delusional depressed group without mood variations. CONCLUSIONS: These results suggest that delusional depressions might have a different neurobiological substrate with loss of chronobiological rhythms.

Antidepressive Agents, Tricyclic↗
PubMed1997

Brofaromine versus imipramine in in-patients with major depression--a controlled trial.

Brofaromine is a selective and reversible inhibitor of monoamine oxidase A. The efficacy and safety of this compound as compared with tricyclic antidepressants, classical monoamine oxidase inhibitors and placebo has been demonstrated in several clinical trials. The present 6-week, double-blind, randomized trial compared brofaromine with imipramine in in-patients with major depression. Brofaromine was as effective as imipramine in the treatment of major depression, but exhibited a different side-effect profile, in particular lacking the anticholinergic and certain cardiovascular side-effects of the tricyclic imipramine, but more likely to induce sleep disturbances. In this study, in-patients were examined, since the majority of controlled clinical trials on depressed patients conducted so far have focused on the evaluation of out-patients. If one assumes that a different degree of severity of depression exists between these two patient groups, then the results of those trials conducted on out-patients cannot readily be transferred to in-patients.

Adolescent↗
PubMed1997

Platelet [3H]imipramine and [3H]paroxetine binding in depressed patients.

[3H]Paroxetine and [3H]imipramine binding to blood platelet membranes was simultaneously measured in 63 control subjects and 18 patients with DSM-III-R criteria for major depression with melancholia. Both binding sites showed significantly different (p < 0.001) maximum binding (Bmax) and equilibrium dissociation constant (Kd) values. Age was not correlated with either [3H]imipramine Bmax or Kd values, but a negative correlation was found between [3H]paroxetine Bmax and age in healthy controls. Furthermore, depressed patients showed significantly lower [3H]imipramine Bmax values (p < 0.001) and higher Kd values (p < 0.001) in comparison to the control group. No differences were observed in [3H]paroxetine Bmax and Kd values between the two groups.

Adult↗
PubMed1998

[3H] imipramine binding in brain samples from depressed suicides and controls: 5-HT uptake sites compared with sites defined by desmethylimipramine.

Using desmethylimipramine (DMI) defined and Na+ dependent [3H]imipramine binding, we have examined both 5-HT uptake sites and sites unrelated to 5-HT uptake, in frontal cortex, putamen and substantia nigra of suicides with a firm retrospective diagnosis of depression and matched controls. No differences were seen between antidepressant-free suicides and controls, although [3H]imipramine binding sites were significantly lower in putamen of the subgroup of non-violent suicides. The number of DMI defined [3H]imipramine binding sites was also significantly lower in putamen of antidepressant-treated suicides.

Adolescent↗
PubMedDate not supplied

Altered [3H]imipramine and 5-HT2 but not [3H]paroxetine binding sites in platelets from depressed patients.

BACKGROUND: Serotonergic system alterations were studied in 51 depressed patients classified according to DSM-III-R criteria for major depression with melancholia compared to 31 healthy controls. METHOD: [3H]Imipramine and [3H]paroxetine binding sites and the 5HT2 receptor were simultaneously determined in blood platelet membranes. RESULTS: A significantly lower maximum binding in [3H]imipramine binding was observed in depressed patients compared to controls (1134+/-74 vs. 1712+/-106 fmol/mg protein, P<0.0001) without changes in the equilibrium dissociation constant (1.10+0.05 vs. 1.25-/+0.09 nM). [3H]Paroxetine binding did not differ between the two groups (Bmax, 1441+/-55 vs. 1280+/-81 fmol/mg protein; Kd, 0.060+/-0.002 vs. 0.062+/-0.002 nM). The K(d) value of 5HT2 binding was lower in depressed patients than controls (0.95+/-0.04 vs. 1.15+/-0.09 nM, P<0.039) without changes in maximum binding (140+/-11 vs. 127+/-14 fmol/mg protein). CONCLUSIONS: Taken together, these results suggest that [3H]imipramine and 5HT2 receptors may be good biological markers for serotonergic dysfunction in depressive disorders.

Adult↗
PubMed2000

Effect of venlafaxine on imipramine metabolism.

The present study was designed to determine the effect of venlafaxine on imipramine metabolism in an attempt to elucidate the potential for cytochrome P450 drug-drug interactions with venlafaxine. We examined the metabolism of a single 100-mg dose of imipramine before and after treatment with venlafaxine, 50 mg three times a day. Eight male subjects were phenotyped for CYP2D6 activity. Two subjects were poor metabolizers of dextromethophan, and data from the remaining six subjects (mean age=45.3+/-15) were analyzed. Venlafaxine increased imipramine C(max) and elevated AUC by 40%. Desipramine clearance and volume of distribution were reduced by 20% and 25%, respectively. These findings are consistent with a statistically significant, but clinically modest impact of venlafaxine on CYP2D6-metabolized substrates.

Adult↗
PubMed1983

Imipramine and chloroquine induced alterations in phospholipid content of rat lung.

The influence of the amphiphilic drugs imipramine (150 mg/kg b. w./day) and chloroquine (75 mg/kg b. w./day) on the phospholipid (PL) -metabolism of rat lung, its PL-content and PL-composition were measured in the cell free lung lavage fluid (alveolar surfactant), in the free alveolar cells (mainly alveolar macrophages), and in the residual lung tissue. In addition to the long-term administration (15 applications during a period of 3 weeks), the influence of short-term administration (2 or 4 applications, resp., during a period of 2 or 4 days) was examined. The alveolar macrophages show the largest increase in PL-content. As revealed by its composition the stored PL are of surfactant origin. In chloroquine treated rats the number of macrophages is increased as well. The concentration of stored PL is higher in macrophages of imipramine treated rats. The excessive accumulation of PL in this animal group possibly impairs the clearance function of alveolar macrophages. This is suggested to be the reason for the accumulation of alveolar surfactant in imipramine treated rats. The influence of the drugs on the PL-content of the residual lung tissue was weak. The results of this study show that amphiphilic drugs cause an accumulation of surfactant-PL within the alveolar macrophages and can promote the alveolar surfactant content even after short-term application. The role of alveolar macrophages in alveolar surfactant catabolism is demonstrated.

Animals↗
PubMed1998

Double-blind evaluation of short-term analgesic efficacy of orally administered diclofenac, diclofenac plus codeine, and diclofenac plus imipramine in chronic cancer pain.

A prospective double-blind randomized trial was conducted on 184 cancer patients with moderate to severe chronic pain to evaluate the analgesic efficacy and tolerability of diclofenac alone (50 mg q.i.d.) or in combination with a weak opioid (codeine 40 mg q.i.d.), or with an anti-depressant (imipramine, 10 or 25 mg t.i.d.). All demographic and clinical characteristics including cancer type, presence of bone metastases, baseline pain severity, neuropathic and nociceptive pain, and depressive state, were well balanced between the three treatment groups. The main analysis of the study was on the VAS scores at visit 2 (day 4). The mean VAS values for both associations imipramine plus diclofenac and codeine plus diclofenac were similar to the association placebo plus diclofenac. Patients on imipramine plus diclofenac and on placebo plus diclofenac were withdrawn mainly for inadequate efficacy, while patients on codeine plus diclofenac discontinued equally for inadequate efficacy or adverse events. In conclusion, in a short-term evaluation the addition of a tricyclic anti-depressant or a weak opioid to diclofenac did not provide further analgesia with respect to diclofenac administration alone.

Administration, Oral↗