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PubMed1984

Adenosine mechanisms are not affected by antidepressant concentrations of desipramine.

We have evaluated the proposal that adenosine may mediate some of the effects of tricyclic antidepressant therapy. In-vitro desipramine (DMI) (1-10 microM) did not affect adenosine or 2-chloroadenosine-induced inhibition of lipolysis or the adenosine stimulated formation of cyclic (c) AMP in the hippocampal slice. However, very high concentrations of desipramine (0.2-0.5 mM) as well as some detergents potentiated the stimulatory effect of adenosine on cAMP formation. The ATP, ADP and AMP contents in slices were unaffected as was the electrically evoked release of purines. Long-term treatment in-vivo with antidepressants in clinically relevant doses did not alter the sensitivity of adenosine receptor mediated cAMP formation in-vitro while the beta-adrenoceptor-mediated formation was depressed by desipramine or imipramine treatment but not by zimelidine or fluoxetine treatment. It is concluded that actions on central adenosine mechanisms are unlikely to play any important role in the therapeutic effects of tricyclic antidepressants.

Adenosine↗
PubMed1986

Functional evidence for altered activity of GABAergic receptors following chronic desipramine treatment in rats.

The antinociceptive effect of subcutaneous 4,5,6,7-tetrahydroisoxazol[5,4-c]pyridin-3-ol (THIP) or (+/-)-baclofen, measured as reaction time of rats placed on a plate heated to 55 degrees C, was assessed after a single or the last repeated (18 consecutive days) dose (5 mg kg-1 once daily) of subcutaneous desipramine. Baclofen (10 mg kg-1)-induced antinociception was reduced by acute and unaffected by chronic desipramine treatment. On the contrary, THIP (20 mg kg-1)-induced antinociception was unaffected by acute and reduced by chronic desipramine.

Analgesics↗
PubMed1987

Biochemical and pharmacological tests for the prediction of ability of monoamine uptake blockers to inhibit the uptake of noradrenaline in-vivo: the effects of desipramine, maprotiline, femoxetine and citalopram.

The ability of desipramine and maprotiline (NA uptake inhibitors), as well as citalopram and femoxetine (5-HT uptake inhibitors) to protect mice against brain NA depletion induced by H 77/77 (4-alpha-dimethyl-m-tyramine), has been compared with their ability to counteract reserpine (2.5 mg kg-1)- or apomorphine (16 mg kg-1)-induced hypothermia and to potentiate TRH (40 mg kg-1)-induced hyperthermia in mice. While both NA uptake inhibitors antagonized the action of H 77/77, maprotiline being weaker than desipramine, femoxetine and citalopram were inactive. However, in contrast to citalopram, femoxetine was active in the other tests, being about twice as weak as maprotiline, which itself was several times weaker than desipramine in those tests. On the basis of the results obtained it is concluded that functional in-vivo tests for NA uptake inhibitors are more sensitive than the H 77/77 biochemical test; moreover, femoxetine, which in-vitro studies is less selective than citalopram, may inhibit the uptake of NA in-vivo.

Animals↗
PubMed1997

Steroid-independent translocation of the glucocorticoid receptor by the antidepressant desipramine.

The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that in its unactivated form resides primarily in the cytoplasm. After being bound by steroid, the GR undergoes a conformational change and translocates to the nucleus, where it influences gene transcription. Because the GR mediates negative feedback exerted by circulating glucocorticoid hormones on the hypothalamic-pituitary-adrenal (HPA) axis, it has been hypothesized that abnormalities in GR expression and/or function may underlie the HPA axis hyperactivity described in patients with major depression. In further support of this hypothesis, animal studies have shown that long term in vivo treatment with antidepressants enhances glucocorticoid feedback inhibition, possibly through a direct effect on the GR. To examine this latter possibility, we evaluated translocation of the GR from the cytoplasm to the nucleus after 24-hr in vitro treatment of L929 cells (mouse fibroblasts) with the tricyclic antidepressant desipramine (0.1-10 microM) in the presence or absence of the synthetic steroid dexamethasone. In addition, GR-mediated gene transcription was measured with the use of L929 cells stably transfected with the mouse mammary tumor virus-chloramphenicol acetyltransferase reporter gene. Desipramine was found to (i) induce GR translocation from the cytoplasm to the nucleus in the absence of steroids (with no effect alone on GR-mediated gene transcription) and (ii) potentiate dexamethasone-induced GR translocation and dexamethasone-induced GR-mediated gene transcription. Treatment with desipramine for 24-96 hr had no effect on the expression of GR protein as measured by cytosolic radioligand receptor binding. We suggest that one important aspect of the effects of antidepressants in vivo may be to facilitate GR-mediated feedback inhibition on the HPA axis, by facilitating GR translocation and function, and thereby reverse glucocorticoid hypersecretion in depression.

Animals↗
PubMed1988

Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine.

Desipramine and several other tricyclic antidepressant drugs reverse chloroquine resistance in Plasmodium falciparum in vitro at concentrations observed in the plasma of human patients treated for depression. Reversal of resistance is associated with increased chloroquine accumulation in the parasite, probably because of inhibition of a putative chloroquine efflux pump. When owl monkeys (Aotus lemurinus lemurinus) infected with chloroquine-resistant Plasmodium falciparum were treated with chloroquine plus desipramine, their parasitemias were rapidly suppressed. Desipramine was found to be one of the most effective compounds yet described for the reversal of chloroquine resistance both in vitro and in vivo.

Animals↗
PubMed1995

Differential effect of desipramine and 2-hydroxydesipramine on depolarization-induced calcium uptake in synaptosomes from rat limbic sites.

This study was conducted to investigate the inhibition of synaptosomal 45Ca uptake by desipramine and its major metabolite 2-hydroxydesipramine in the rat hippocampus and cingulate cortex, areas associated with emotional control. A concentration-dependent inhibition of net depolarization-induced 45Ca uptake was observed for desipramine (20-200 microM) in synaptosomes from both sites. However, 20 microM 2-hydroxydesipramine failed to inhibit calcium channel function in either of the two limbic sites; higher concentrations (60 or 200 microM) did produce a minor degree of inhibition in hippocampus synaptosomes. Others have shown that the clinically encountered plasma concentrations of 2-hydroxydesipramine are lower than those of desipramine, and the brain concentration of 2-hydroxydesipramine is therefore not expected to surpass or even reach 20 microM. In view of the previously observed clinical activity of 2-hydroxydesipramine, the present results indicate that calcium channel antagonism may not be the basis for the therapeutic effect of tricyclic antidepressants.

Animals↗
PubMed1989

Neuroendocrine response to clomipramine and desipramine--the evidence of partial determination by heredity and sex.

A single dose of clomipramine, 10 mg i.v., or desipramine, 25 mg i.m., was administered to seven healthy young sibling pairs in a randomized cross-over experiment. The response of serum growth hormone, prolactin and cortisol was measured. The main findings were (1) sex differences in the growth hormone and cortisol response to desipramine and (2) a significant genetic component of the prolactin and cortisol response to desipramine as indicated by significantly (p less than 0.05) lower within-pair than between-pair variance in the sibling pairs but not random pairs of the experimental subjects.

Adult↗
PubMed1994

Catalase, superoxide dismutase and glutathione peroxidase activity in neutrophils of sham-operated and olfactory-bulbectomised rats following chronic treatment with desipramine and lithium chloride.

In the olfactory-bulbectomised rat model of depression, neutrophil phagocytosis was significantly decreased and phagocytosis started later in comparison to sham-operated animals. Both desipramine and lithium chloride treatment significantly reversed the depressed neutrophil phagocytosis and shortened the time to commencement of phagocytosis in drug-treated bulbectomised rats. The catalase and glutathione peroxidase (GSH-PX) activities in bulbectomised rats were decreased, while superoxide dismutase (SOD) was significantly increased. Chronic desipramine and lithium chloride treatment slightly improved catalase activity in the bulbectomised rats. Desipramine significantly reversed the reduction in activity of GSH-PX, but failed to reverse the increased activity of SOD. In contrast, lithium chloride significantly reversed SOD activity to normal values, without affecting GSH-PX activity in the bulbectomised rats.

Animals↗
PubMed1977

Influence of desipramine on the uptake and efflux of radiolabelled bretylium and bethanidine in the adventitial and media-intimal layers of rabbit aortic strips.

The desipramine-sensitive uptake (neuronal uptake) of 14C-bretylium and 14C-bethanidine into the rabbit aortic adventitial layer from 3 X 10(-6) M solutions increased with time during a 20 min incubation. For both compounds a neuronal uptake of 50 pmol/50 mg wet weight adventitia was associated with 10% block of the contractile response to field stimulation at 16 Hz and 150 pmol/50 mg with 60% block. The concentration of blocking agents inside the neuron at 50% blockade was calculated to be 260 X 10(-6) M, an 87-fold increase over the medium. The bretylium in the neuron decreased by 50% during 20 min washout, and bethanidine by 29%. Desipramine when added to the bath 20 min following the addition of the blocking agents led to a loss of bretylium but not of bethanidine from the adventitia. Desipramine had little or no effect on the uptake, washout or disposition of either blocking agent in the media-intimal layers. The data indicate that bretylium has a greater propensity than bethanidine to be lost from the neurons; however, it appears to be recycled back through the membrane via the amine pump more readily than bethanidine. The fact that conservative calculations indicate that the neuronal membrane slowly established a concentration of the blocking agents within the neuron that is known to produce rapid local anesthesia when topically applied to adrenergic nerve trunks and which approaches a concentration needed to inhibit sensory endings suggests that local anesthesia may play a role in the mechanism of neuron blockade.

Animals↗
PubMed1980

Neuroloeptic effect on desipramine steady-state plasma concentratins.

The authors examined the effect of neuroleptic drugs on desipramine steady-state plasma concentration in 30 patients who received similar milligram per kilogram doses of desipramine. Fifteen of these patients also received a neuroloeptic drug and had desipramine plasma levels twice that of the 15 patients who received dispiramine alone. The authros discuss the implications of the magnitude of this difference for therapeutic response and incidence of side effects.

Adult↗
PubMed1983

The methylphenidate test for differentiating desipramine-responsive from nortriptyline-responsive depression.

Monitoring tricyclic antidepressant concentrations in the plasma of 43 patients with major depressive disorders indicated that some responded to imipramine or desipramine but not to amitriptyline or nortriptyline, or vice versa, even though plasma levels were within therapeutic ranges. Mood elevation by methylphenidate predicted marked improvement from treatment with imipramine or desipramine but not with amitriptyline or nortriptyline. When methylphenidate failed to improve mood, patients responded to amitriptyline or nortriptyline but not to desipramine. These results suggest differential drug responses with different tricyclic antidepressants, the clinical utility of the methylphenidate test, and the heterogeneity of depressions. The authors question the mechanism of action of nortriptyline via blockade of norepinephrine reuptake.

Adolescent↗
PubMed1986

Desipramine and 2-hydroxydesipramine in human breast milk and the nursing infant's serum.

Desipramine and its metabolite 2-hydroxydesipramine were measured in the milk of a nursing mother and in the plasma of the mother and infant during administration of 300 mg/day of desipramine to the mother. Similar concentrations of both compounds were found in maternal plasma and milk. A pharmacokinetic plot of the milk over 24 hours showed the expected rise and fall of the substances following a single nighttime dose. Neither parent compound nor metabolite could be detected in the infant's serum even though the measurements were made shortly after peak ingestion by the infant. Furthermore, no clinical signs of toxicity were observed in the infant after 3 weeks of treating the mother with desipramine.

Adult↗
PubMed1997

Addition of desipramine to serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder.

OBJECTIVE: The purpose of this study was to determine whether combined treatment with a selective serotonin reuptake inhibitor (SSRI) and a norepinephrine reuptake inhibitor, desipramine, effectively reduces obsessive-compulsive symptoms in patients who do not respond to SSRIs. METHOD: In a double-blind study, desipramine or placebo was added for 6 or 10 weeks to the treatment of 30 patients with obsessive-compulsive disorder whose symptoms were refractory to SSRI treatment (fluvoxamine, fluoxetine, or sertraline) alone. RESULTS: There were no significant differences between the adjunctive desipramine and placebo groups in obsessive-compulsive or depressive symptoms. CONCLUSIONS: These data suggest that clomipramine's possibly superior efficacy in the treatment of obsessive-compulsive symptoms may not stem from its capacity to inhibit reuptake of norepinephrine.

1-Naphthylamine↗
PubMed2000

Different effect of desipramine on locomotor activity in quinpirole-treated rats after repeated restraint and chronic mild stress.

We have studied the effect of chronic treatment with the tricyclic antidepressant drug desipramine on locomotor activity in rats challenged with the administration of the D2-like dopamine agonist quinpirole, after prolonged exposure to two different stress regimens, repeated restraint stress and chronic mild stress (different stressors randomly presented). These stress schedules have been previously reported to influence in opposite ways the sensitivity to the locomotor response mediated by the stimulation of mesolimbic dopamine receptors. In particular, repeated restraint has been reported to induce an increased response to the locomotor effect of amphetamine, while chronic mild stress has been reported to induce a decreased locomotor response to quinpirole. In the present study, repeated restraint stress failed to influence the locomotor activity after challenge with quinpirole, while chronic mild stress reduced this response. Chronic treatment with desipramine failed to influence this response in the control group, but exerted opposite effects in the two stressed groups. In particular, chronic desipramine reduced locomotor activity in quinpirole-treated rats in the restraint stress group, and increased it in the chronic mild stress group, thus preventing the subsensitivity induced by this stress regimen. The present results, taken together with results from earlier studies, are consistent with the hypothesis that the effect of antidepressants on the sensitivity of the mesolimbic dopamine receptors mediating the locomotor behavioural response tends to be opposite with respect to that exerted by stress, regardless of its direction. However, since we failed to show an increased locomotor activity after quinpirole challenge in the repeated restraint group, this hypothesis remains to be demonstrated. The two stress schedules reduced body weight gain in a similar way, therefore their different effects do not seem to be due to a difference in stress severity. Thus, the observation that both stress schedules reduced body weight gain in a similar way, but only chronic mild stress reduced the sensitivity to the locomotor response to quinpirole, shows that this effect is not an artefact of body weight decrease.

Animals↗
PubMed1987

A grand mal seizure associated with desipramine and haloperidol.

Authors describe a case of grand mal seizure associated with administration of desipramine and haloperidol. Neuroleptic induced inhibition of desipramine metabolism is discussed as a possible explanation of unusually high desipramine plasma level of 610 ng/ml at the day of seizure.

Adult↗
PubMed1996

ECG changes in pediatric patients on tricyclic antidepressants, desipramine, and imipramine.

OBJECTIVE: To determine if there is an altered pattern of cardiac electrical activity in children treated with tricyclic antidepressants, desipramine, or imipramine, which may predispose these patients to sudden death. METHODS: All patients in a child psychiatry practice from 1989 to 1993 in Calgary, Alberta, treated with desipramine or imipramine with both pre- and post-treatment electrocardiograms (ECGs) were included in the study (n = 21; ages 8 to 17 years). Thirty-six blinded post-treatment ECGs were analysed for interval measurement and compared to the pretreatment ECGs. RESULTS: Drug dosages ranged from 25 mg to 125 mg per day and treatment duration ranged from 1 to 49 months. Seven of 21 patients were concurrently receiving an antipsychotic medication (pericyazine). The maximal increase in PR, and QRS, and QT interval changes were 40 msec and 70 msec, respectively, with most patients demonstrating no significant changes in the ECG intervals. The QT interval was corrected for heart rate (QTc). No significant arrhythmias or tachycardias were observed. ECG interval changes were not related to drug dosage, age, treatment duration or plasma levels. CONCLUSIONS: No consistent pattern of ECG interval changes including the QTc interval was observed in children on desipramine and imipramine.

Adolescent↗
PubMed1980

The peripheral anticholinergic activity of tricyclic antidepressants: comparison of amitriptyline and desipramine in human volunteers.

The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine, and of placebo, were compared on a range of cholinergic functions (resting pupil diameter, pilocarpine-evoked miosis, baseline-sweating, carbachol-evoked sweating, salivation, heart rate) in eight healthy volunteers. Three measures (pilocarpine-evoked miosis, carbachol-evoked sweating and salivation) reflected the antimuscarinic property of the antidepressants; in two tests (pilocarpine-evoked miosis and salivation) amitriptyline appeared to be more potent than desipramine. Resting pupil diameter was not affected by amitriptyline, whereas desipramine caused mydriasis, indicating that pupil size is not a reliable measure of anticholinergic activity in the case of drugs which also affect adrenergic mechanisms. Baseline-sweating and heart rate were not affected by the antidepressants.

Adult↗