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PubMed1984

Attenuation of the post-decapitation convulsions after repeated treatment of rats with desipramine, imipramine and maprotiline.

The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post-decapitation convulsions (PDC's) after repeated administration of 10 mumol/kg orally twice daily, or 66 mumol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.

Alanine↗

PubMed1985

Opioid peptides and receptors in relation to affective illness. Effects of desipramine and lithium on opioid receptors in rat brain.

A brief review is given of clinical and experimental evidence supporting the notion that opioid peptides and opioid receptors play a role for the regulation of mood and activity, and that they could be involved in the pathophysiology of affective illness and the action of antimanic and antidepressant treatment modalities. We have carried out in vitro and in vivo studies on the effects of desipramine and lithium on opioid receptors in rat brain. In vitro desipramine inhibited the binding of 3H-enkephalinamide to neuronal membranes (P2-fractions) through mechanisms not yet known. Treatment with desipramine in vivo (10 mg/kg body weight/day) caused a down-regulation of 3H-enkephalinamide binding in the basal ganglia and the hippocampus, while no effects could be observed in the cerebral cortex and the rest of the forebrain. In vitro addition of lithium inhibited enkephalin binding to opioid receptors through a reduction in the number of binding sites, while the affinity remained unchanged or was changed only slightly. Treatment with lithium in vivo for three weeks with lithium doses providing serum lithium concentrations of about 1 mM also caused a down-regulation in the number of opioid binding sites in the cerebral cortex, the hippocampus, and the basal ganglia, while no changes could be observed in affinity. The studies suggest that desipramine and lithium, both effective in the treatment of manic-depressive illness, may share certain actions on opioid receptors in the brain.

Animals↗

PubMed2006

Inhibition of nonexocytotic norepinephrine release by desipramine reduces myocardial infarction size.

During myocardial ischemia, a substantial accumulation of norepinephrine occurs in the ischemic zone due to a local nonexocytotic release of norepinephrine. Norepinephrine release is driven by the neuronal monoamine transporter (NET), which reverses its usual transmembrane transport direction. We investigated whether this local accumulation of norepinephrine contributes to irreversible myocardial injury in an in vivo model of myocardial infarction. Male, anaesthetized Wistar rats were subjected to 30 min coronary occlusion and subsequent 120 min reperfusion. Five minutes prior to coronary occlusion, the NET inhibitor desipramine was administered intravenously. Infarct size (IS) was determined by TTC-staining and was related to the area at risk (AAR). The influence of desipramine on cardiac norepinephrine release was investigated in isolated perfused hearts with 30 min of regional ischemia. Norepinephrine was measured in the effluent from the hearts by HPLC and electrochemical detection. Desipramine (0.1-0.8 mg/kg) dose-dependently reduced infarct size (IS/AAR) from 0.54 to 0.21 and suppressed postischemic norepinephrine release from 245 to 108 pg/mL. In summary, the data indicate that nonexocytotic release of norepinephrine in myocardial ischemia exaggerates acute ischemic damage, because suppression of ischemia-induced release of norepinephrine by the tricyclic antidepressant desipramine effectively reduces infarct size in an in vivo model of myocardial ischemia.

Adrenergic Uptake Inhibitors↗

PubMed2005

Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy.

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.

Animals↗

PubMed2002

Differential pre- and postsynaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF.

Right heart failure (RHF) is characterized by chamber-specific reductions of myocardial norepinephrine (NE) reuptake, beta-receptor density, and profiles of cardiac sympathetic nerve ending neurotransmitters. To study the functional linkage between NE uptake and the pre- and postsynaptic changes, we administered desipramine (225 mg/day), a NE uptake inhibitor, to dogs with RHF produced by tricuspid avulsion and progressive pulmonary constriction or sham-operated dogs for 6 wk. Animals receiving no desipramine were studied as controls. We measured myocardial NE uptake activity using [(3)H]NE, beta-receptor density by [(125)I]iodocyanopindolol, inotropic responses to dobutamine, and noradrenergic terminal neurotransmitter profiles by glyoxylic acid-induced histofluorescence for catecholamines, and immunocytochemical staining for tyrosine hydroxylase and neuropeptide Y. Desipramine decreased myocardial NE uptake activity and had no effect on the resting hemodynamics in both RHF and sham animals but decreased myocardial beta-adrenoceptor density and beta-adrenergic inotropic responses in both ventricles of the RHF animals. However, desipramine treatment prevented the reduction of sympathetic neurotransmitter profiles in the failing heart. Our results indicate that NE uptake inhibition facilitates the reduction of myocardial beta-adrenoceptor density and beta-adrenergic subsensitivity in RHF, probably by increasing interstitial NE concentrations, but protects the cardiac noradrenergic nerve endings from damage, probably via blockade of NE-derived neurotoxic metabolites into the nerve endings.

Adrenergic Uptake Inhibitors↗

PubMed1991

Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans.

In isolated organs, or when given in low dose intra-arterially, tricyclic antidepressant drugs are known to block reuptake of norepinephrine into sympathetic nerve varicosities, with a resultant increased norepinephrine washout. On the other hand, systemic administration of such drugs in humans reduces norepinephrine spillover to plasma. To clarify these seemingly contradictory findings, we have measured concurrently muscle sympathetic activity in the peroneal nerve (microneurography) and rates of norepinephrine spillover to plasma for the body as a whole and for the heart, the kidneys, and the forearm (radiotracer technique), both before and after intravenous infusion of desipramine, 0.5 mg/kg. Desipramine lowered the overflow of norepinephrine to plasma for the body as a whole and from the forearm and the kidneys (by 30-50%) but increased cardiac norepinephrine spillover by 25%. Both the number of sympathetic bursts per min in the peroneal nerve and their mean voltage amplitudes were markedly reduced after desipramine; total activity (bursts/min x mean burst amplitude) fell by approximately 90%. The effects of desipramine on norepinephrine spillover are explicable in terms of inhibition of central sympathetic outflow, balanced against the local blockade of transmitter reuptake. In most sites, the predominant effect is a reduction of norepinephrine overflow. For the heart, where reuptake is so important in transmitter disposition, the net effect is increased overflow.

Adult↗

PubMed1999

Contribution of lungs to desipramine-induced changes in whole body catecholamine kinetics in newborn lambs.

To characterize pulmonary and total body norepinephrine and epinephrine kinetics in the immediate newborn period, the effects of desipramine were studied in six fetal lambs chronically instrumented at 133-134 days gestation (term 147 days) and delivered 1 wk later by cesarean section under spinal anesthesia. Norepinephrine and epinephrine kinetics were determined with isotope dilution methodology 4 h after birth and repeated 30 min after desipramine (2 mg/kg iv). At baseline, the lungs accounted for 35 +/- 10 and 47 +/- 13% of whole body norepinephrine clearance (93 +/- 8 ml. min-1. kg-1) and spillover (188 +/- 29 ng. min-1. kg-1) and 15 +/- 2 and 19 +/- 7% of whole body epinephrine clearance (82 +/- 4 ml. min -1. kg -1) and release (22.7 +/- 2.7 ng. min-1. kg-1), respectively. Desipramine decreased pulmonary norepinephrine and epinephrine clearance and spillover to near-zero levels, whereas whole body norepinephrine clearance fell by 51 +/- 3% (P < 0.001), norepinephrine spillover by 54 +/- 6% (P < 0.005), epinephrine clearance by 30 +/- 6% (P < 0.01), and epinephrine spillover by 34 +/- 11% (P < 0.05). These results indicate that, in the immediate newborn period, pulmonary removal and release of norepinephrine and epinephrine is mediated by a desipramine-sensitive process that accounts for a major portion of associated reductions in whole body norepinephrine and epinephrine clearance and release.

Animals↗

PubMed2000

Effect of tolcapone on the haemodynamic effects and tolerability of desipramine.

BACKGROUND AND PURPOSE: To determine the changes in haemodynamics, tolerability and pharmacokinetics that may occur when a combination of tolcapone and levodopa/carbidopa are given with desipramine. METHODS: In a crossover study, 22 healthy subjects received desipramine during two 13-day treatment periods (25 mg t.i.d. for 3 days and 50 mg t.i.d. for 10 days), with a washout period of 10-15 days. Subjects received levodopa/carbidopa (100 mg/25 mg t.i.d. for 5 days, days 9-13) and concomitant, double-blind, randomized treatment with either tolcapone (200 mg t.i.d.) or placebo. RESULTS: No significant pharmacodynamic and pharmacokinetic interactions occurred between tolcapone and desipramine. Adverse events were predictable based on the known effects of the individual drugs. CONCLUSIONS: Tolcapone can be combined with levodopa/carbidopa and desipramine in patients with Parkinson's disease.

Adult↗

PubMed2005

Effects of desipramine and escitalopram on postprandial symptoms induced by the nutrient drink test in healthy volunteers: a randomized, double-blind, placebo-controlled study.

BACKGROUND: Antidepressants are widely used to treat functional gastrointestinal disorders but their effect on postprandial symptoms remains unstudied. We hypothesized that desipramine and escitalopram would enhance the maximum tolerated volume of nutrient ingested and decrease postprandial symptoms. METHODS: Healthy participants (n=45) all underwent an assessment of symptoms, anxiety and depression, and a standard nutrient drink test (Ensure). Participants were randomized to 11 days of desipramine (50 mg once daily), escitalopram (10 mg once daily) or identical placebo. RESULTS: The maximum tolerated gastric volumes were not significantly different on day 11 for desipramine (1,136+/-478 ml, mean+/-SD), escitalopram (1,198+/-422 ml) and placebo (1,231+/-318 ml). A univariate analysis indicated significant treatment group effects on total symptom scores (p=0.049), but after adjusting for age, gender, BMI and baseline scores, treatment effects were no longer significant (p=0.15). CONCLUSIONS: While this study does not rule out a beneficial effect of tricyclics or selective serotonin reuptake inhibitors in functional dyspepsia, neither desipramine nor escitalopram significantly altered the nutrient volume ingested or symptoms induced by the nutrient drink test in healthy volunteers.

Adult↗

PubMed1996

Effects of chronic exposure to desipramine and mianserin on Ca2+ mobilization induced by noradrenaline, acetylcholine, and high K+ in rat frontocortical neurons.

We examined the chronic effects of desipramine and mianserin on increases of intracellular Ca2+ concentration ([Ca2+]i) induced by noradrenaline (NA), acetylcholine (ACh), or high K+ in cultured neurons of rat frontal cortex, using fluoromicroscopic analysis with Ca(2+)-sensitive dye fura-2. NA- and ACh-induced [Ca2+]i increases were abolished in the presence of 1 microM prazosin and 1 microM atropine, respectively, and partially inhibited in the absence of extracellular Ca2+. When cultures were treated with 1 microM desipramine for 5 days, the dose-dependent curves of NA- and ACh-induced (0.01-100 microM) [Ca2+]i increases were similar to those of the control cultures. Neither NA- nor ACh-induced [Ca2+]i increases were affected by desipramine exposure, even at a concentration of 10 microM. Treatment with mianserin (0.1, 1, or 10 microM) for 5 days had no effect on either NA- or ACh-induced [Ca2+]i increases. Additionally, [Ca2+]i increases induced by high K+ (12.5-50 mM) were not affected following chronic 10 microM desipramine exposure for 5 days. Thus, chronic antidepressant exposure does not modify the [Ca2+]i increased mediated by alpha 1-adrenoceptors, muscarinic cholinergic receptors, or voltage-sensitive Ca2+ channels. Changes in Ca2+ mobilization may not be one of the mechanisms of antidepressants.

Acetylcholine↗

PubMed1990

High- and low-affinity [3H]desipramine-binding sites in human postmortem brain tissue.

The binding of [3H]desipramine to human brain tissue was characterized. Competition studies in the frontal cortex and hypothalamus revealed a single-site binding model for noradrenaline (Ki 120-190 microM). The noradrenaline uptake inhibitors nisoxetine, nortriptyline and desipramine fitted two-site binding models and these compounds exhibited 10-80 times lower Ki values than the serotonin uptake inhibitor citalopram. The high-affinity component of the nisoxetine-sensitive [3H]desipramine binding (Ki 50-110 nM) approximated the binding sensitive to noradrenaline. This binding fraction was defined as that sensitive to 1 microM nisoxetine and showed a maximum binding capacity (Bmax) of 380 +/- 80 fmol/mg protein and an apparent Kd of 5.1 (4.5-5.7) nM in the hypothalamus. The binding was also investigated in 25 additional brain regions without finding detectable amounts of binding. However, when the specific binding was defined as that sensitive to 100 microM nisoxetine, low-affinity binding where Bmax and Kd were not possible to determine was obtained in all brain regions investigated. It is concluded that [3H]desipramine binding to human brain tissue represents multiple binding sites. Only when regarding binding sensitive to noradrenaline and to the high-affinity component of noradrenaline uptake inhibitors is the binding saturable and of high affinity. It is possible that this site represents the uptake site for noradrenaline.

Adult↗

PubMed1990

Desipramine blocks augmented neurogenic vasoconstrictor responses to epinephrine.

The forearm vasoconstrictor response to lower body negative pressure (LBNP), a reflex stimulus to norepinephrine release, can be augmented by a prior brachial artery infusion of epinephrine. We wished to determine whether this sustained aftereffect of epinephrine could be replicated by systemic infusion and, if so, whether it could be prevented by prior uptake-1 blockade with desipramine. Eight normal men (mean age 30 years) were studied on two separate study days at least 1 week apart, 2.5 hours after taking, at random, either desipramine (125 mg p.o.) or placebo. Forearm vascular resistance was measured at rest and at the end of 6 minutes of LBNP at -40 mm Hg. This was done both before and 30 minutes after a 60-minute infusion of epinephrine (1.5 micrograms/min i.v.). From similar baselines, the forearm vasoconstrictor response to LBNP was significantly augmented 30 minutes after epinephrine on the placebo day (+17 +/- 4 vs. +12 +/- 3 resistance units, mean +/- SEM, p less than 0.01) but not on the desipramine day (+14 +/- 2 vs. +16 +/- 3 resistance units). The heart rate response to LBNP was also greater after epinephrine on the placebo day (+20 +/- 3 vs. +16 +/- 2 beats/min, p less than 0.05). Mean arterial pressure was higher after epinephrine infusion on the placebo (p less than 0.01) but not on the desipramine day.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1986

Neuroleptic dose and desipramine concentrations during combined treatment of unipolar delusional depression.

The relationship of response to neuroleptic dose and desipramine plasma concentration was examined in 31 patients with unipolar delusional depression. The patients received either perphenazine or haloperidol for 1-2 weeks, after which desipramine, 2.5 mg/kg of body weight per day, was added. Neuroleptic dose varied among patients but was constant within individuals. Global response was rated retrospectively on the basis of outcome during the fourth week of combined drug treatment. Responders had higher plasma desipramine concentrations and had received higher neuroleptic doses than nonresponders had. The effective threshold level for desipramine was similar to that previously described for nonpsychotic melancholic patients, suggesting a similar mode of action for the drug in the two disorders.

Administration, Oral↗

PubMed1998

Repeated administration of fluoxetine, desipramine and tranylcypromine increases dopamine D2-like but not D1-like receptor function in the rat.

We tested the effect of repeated treatment (twice daily for 14 days) of rats with the antidepressant drugs fluoxetine, desipramine and tranylcypromine, on the behavioural response to the non-selective dopamine (DA) receptor agonist, apomorphine, the D1-like receptor agonists, SKF 38393 and SKF 81297 and the D2-like receptor agonists, RU 24213 and quinpirole. Agonist-induced behaviour was monitored by automated activity meters and direct observation using a checklist scoring method. Fluoxetine, desipramine and tranylcypromine enhanced (albeit to a varying degree) the behavioural responses to apomorphine (0.75 mg/kg, s.c.), quinpirole (0.25 mg/kg, s.c.) and RU 24213 (0.75 mg/kg, s.c.). In contrast, fluoxetine, desipramine and tranylcypromine did not increase the behavioural responses to SKF 38393 (7.5 mg/kg, s.c.) and SKF 81297 (0.5 mg/kg, s.c.). Finally, fluoxetine, despiramine and tranylcypromine did not modify the behavioural responses to the concomitant administration of SKF 38393 (7.5 mg/kg, s.c.) and quinpirole (0.25 mg/kg, s.c.). Our data suggest that repeated administration of fluoxetine, desipramine and tranylcypromine increases central DA D2-like but not D1-like receptor function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2004

Depressive symptoms and alcohol consumption among nonalcoholic depression patients treated with desipramine.

OBJECTIVE: There are few data addressing the effect of alcohol consumption on response to antidepressants among nonalcoholics with depression. Similarly, the effect of antidepressant treatment on alcohol consumption in this group is not yet understood. This study focuses on changes in depressive symptoms and alcohol consumption in response to treatment with desipramine. METHOD: Twenty-seven nonalcoholic outpatients with major depression (as determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime Version) completed measures of depression (that is, the 17-item Hamilton Depression Rating Scale and the Beck Depression Inventory) and alcohol consumption at intake and after 5 weeks of open treatment with desipramine. Subjects were characterized as minimal or mild-to-moderate drinkers. RESULTS: There was no significant difference between the groups with respect to effectiveness of antidepressant treatment. Analysis for repeated measures demonstrated that alcohol consumption with desipramine was significantly lower after treatment than at intake (F = 4.8, df 23:2, P < 0.01). Further, carbohydrate consumption was also significantly lower after treatment than at intake (F = 4.4, df 23:2, P < 0.05). CONCLUSIONS: Desipramine treatment appeared to result in decreases in alcohol consumption in nonalcoholic patients with depression. Further research is needed to elucidate the effect of alcohol consumption on the course and outcome of major depressive illness among nonalcoholics as well as the effect of antidepressant medication on alcohol consumption in this population.

Adult↗

PubMed1984

Massive eosinophilic reaction to desipramine in conjunction with pneumonia.

The authors report on a female patient with bipolar affective disorder who presented with marked eosinophilia in conjunction with pneumonia five days after a medication change from amitriptyline to desipramine (for intolerable dry mouth). She improved with discontinuance of medications and supportive management, and her eosinophilia normalized. Reinstitution of desipramine was followed by prompt appearance of asymptomatic eosinophilia, which resolved with discontinuation of desipramine. A subsequent depression managed with amitriptyline was followed by no abnormal white blood count findings. Eosinophilia is occasionally encountered in imipramine or desipramine therapy and, although usually asymptomatic, appears to be manageable by switching to amitriptyline or nortriptyline.

Aged↗

PubMed1986

Desipramine plasma concentration and therapeutic response in elderly depressives: a naturalistic pilot study.

This naturalistic pilot study of desipramine hydrochloride treatment in elderly DSM III diagnosed depressives demonstrated that therapeutic response was related to desipramine plasma levels and that a desipramine plasma concentration of 200 nmol/l significantly differentiated responders from non-responders. Plasma concentrations of 2-Hydroxydesipramine were not related to therapeutic response. This finding suggests that monitoring of desipramine plasma levels has utility in certain clinical situations. Further fixed dosage studies are necessary to confirm these initial results.

Aged↗

PubMed1988

A comparison of the efficacy and safety of alprazolam and desipramine in depressed outpatients.

Fifty-two adult depressed outpatients fulfilling Research Diagnostic Criteria for Definite Major Depressive Disorder were enrolled in a double-blind study comparing the antidepressant effects of alprazolam versus desipramine. Twenty-nine patients completed the seven week (one week placebo followed by six weeks of active drug) study. The mean daily dose of alprazolam and desipramine at study termination was 3.34 mg and 192 mg respectively. Based on psychometric ratings of depression (Hamilton Scale) and severity of illness (Clinical Global Impressions) there was no significant difference between alprazolam and desipramine at the end of six weeks of active drug treatment. Both medications were well tolerated with drowsiness being the most common side effect of alprazolam, and insomnia, dry mouth, and constipation, the complaints most associated with desipramine.

Adult↗