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PubMed1985

Imipramine and desipramine disposition in the elderly.

Forty-six healthy male and female volunteers aged 21 to 88 received single 12.5-mg i.v. doses of imipramine, and 35 of these people received single 50-mg p.o. imipramine doses on a different occasion. Thirty-five similar volunteers received single 50-mg p.o. desipramine doses. Among these subjects 25 participated in studies of both imipramine and desipramine. Kinetic variables for the respective drugs were determined from multiple plasma drug concentrations from samples obtained during 96 hr after the dosage. Imipramine half-life was markedly prolonged in elderly vs. young males (28.6 vs. 16.5 hr; P less than .001) and females (30.2 vs. 17.8 hr; P less than .01) due to decreased clearance (males: 567 vs. 945 ml/min, P less than .01; females: 599 vs. 975 ml/min, P less than .005) with no change in volume of distribution. After p.o. imipramine doses time to peak imipramine concentration was shorter in elderly females (2.1 vs. 4.8 hr; P less than .005) but no different in males. Peak concentration achieved was greater in the elderly of both sexes (males: 40.2 vs. 19.5 ng/ml, P less than .005; females: 44.7 vs. 10.4 ng/ml, P less than .01). Comparison of p.o. and i.v. imipramine doses indicated no difference in absolute bioavailability between the elderly and young of either sex. In contrast, after p.o. desipramine more limited age-related changes were noted. Desipramine half-life was slightly prolonged in elderly males (30.8 vs. 21.2 hr; P less than .05) apparently related to a nonsignificant decrease in p.o. clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1981

Quantitative mapping of metabolites of imipramine and desipramine in plasma samples by gas chromatographic-mass spectrometry.

Imipramine and desipramine are known to metabolize primarily by demethylation and hydroxylation. Hydroxy metabolites, 2-hydroxyimipramine and 2-hydroxydesipramine, are reported to be pharmacologically active by in vitro studies. We now report a simple gas chromatographic-mass spectrometric selected ion-monitoring (SIM) method for hydroxy metabolites of imipramine and desipramine from plasma samples using deuterated analogues as internal standards. d4-Internal standards for imipramine, desipramine, and their 2-hydroxy derivatives, were prepared in our laboratory and added to plasma samples, extracted at pH 9 with ethyl acetate, then at pH greater than 11 with hexane-isopropanol. The extracts were combined and evaporated under nitrogen. The trifluoroacetyl derivatives were prepared using N-methyl-bis-trifluoroacetamide and analyses were performed using GC-MS selected ion-monitoring in the electron ionization mode. Hydroxylation to 2-hydroxy metabolites varied widely between subjects. We also noticed in vivo methylation of desipramine to imipramine as a pathway of its metabolism in 15% of the subjects. It is suggested that plasma levels of all active metabolites must be considered in the assessment of the relationship of plasma levels of the drug to clinical response.

Biotransformation↗

PubMed1994

A double-blind trial of bupropion versus desipramine for bipolar depression.

BACKGROUND: Although treatment of bipolar depression is a frequent clinical problem, double-blind studies of the treatment of bipolar depression are scarce. Some case series and uncontrolled data suggest antidepressants may differ in their propensity to induce mania or their efficacy for bipolar depression. METHOD: The authors conducted a prospective double-blind trial to assess efficacy and rate of treatment-emergent mood elevation in depressed bipolar patients when bupropion or desipramine was added to an ongoing therapeutic regimen of lithium or an anticonvulsant. Results were assessed after 8 weeks of acute treatment and during maintenance treatment up to 1 year. RESULTS: No difference was found for acute efficacy between the two drugs. Mania/hypomania was observed in 5 of 10 desipramine-treated patients, but only 1 of 9 bupropion-treated patients. The occurrence of hypomania or mania was correlated with treatment group (Kendall's tau correlation = 0.42; Z = -2.5, p < .012). CONCLUSION: These pilot findings suggest that bupropion is less likely to induce mood elevation than desipramine. For treatment of bipolar depression, bupropion and desipramine appear to have similar antidepressant efficacy.

Adult↗

PubMed1994

Continuity of care and desipramine in primary cocaine abusers.

The objective of this research was to determine the efficacy of enhanced continuity of care and desipramine in increasing treatment attendance and abstinence from cocaine in primary cocaine abusers. Study design was a random assignment, placebo-controlled factorial with assessments at baseline and at 3 (first week of outpatient treatment), 8, and 12 weeks after start of study. Desipramine blood levels were taken at weeks 2 (inpatient), 3, and 8. Subjects (N = 94 men) were recruited on an inpatient ward and assigned to increased continuity of care or to standard treatment, and to active or placebo drug. Main outcome variables were toxicology-verified reports of cocaine use, and attendance at counseling sessions. Enhanced continuity of care increased abstinence from cocaine at week 3 and increased attendance at individual counseling sessions throughout the 12 weeks of the study. There were no main effects for desipramine. Blood levels above 123 ng/ml at week 2 predicted longer stays in outpatient. We conclude that enhanced continuity of care is a low cost intervention that improves early treatment outcome and attendance; desipramine effects do not warrant its therapeutic use.

Adult↗

PubMed1994

Pharmacogenetics of desipramine metabolism.

There is wide interindividual variation in steady-state plasma concentration of desipramine and other tricyclic antidepressants primarily due to differences in rates of hydroxylation. Several studies have shown that the rate of hydroxylation of desipramine is correlated with the rate of hydroxylation of the genetic probe drug, debrisoquine, which is controlled by monogenic inheritance. However, no population studies of the polymorphic metabolism of antidepressants have been reported. In this study, 59 patients with endogenous depression received a fixed dose of desipramine and the steady-state plasma concentration of desipramine and 2-hydroxydesipramine were determined by high-pressure chromatography. A new statistical approach based on optimizing the fit to a specific stochastic model was utilized to separate the mixture of the three genotypes: homozygous extensive (AA), heterozygous extensive (Aa) and poor (aa) metabolizers. The proportions of the genotypes are 0.43, 0.45 and 0.12, respectively. The gene frequency of the low-activity allele is 0.34 and that of the high-activity allele is 0.66. The means (SD) of the desipramine/2-hydroxydesipramine metabolic ratios of the three genotypes are 1.71 (0.44), 3.32 (1.68) and 23.32 (10.03). These data suggest that the heterozygous genotype has half the metabolic activity of the homozygous extensive metabolizer and that the poor metabolizer genotype has negligible metabolic activity.

Adolescent↗

PubMedDate not supplied

Administration of desipramine at infancy reduces dorsal striatal serotonin metabolism at adolescence in the rat.

Desipramine, a monoamine uptake inhibiting antidepressant, was given at infancy to male and female rats and the effects of its administration on the metabolism of dorsal striatal monoamines at adolescence were examined. Desipramine, 5 mg/kg s.c., was administered once a day from the 6th to the 20th postnatal day. Rats were decapitated at the postnatal age of one month and the concentrations of monoamines and their metabolites in dorsal striata were analyzed using high performance liquid chromatography with electrochemical detection. Desipramine decreased the concentration of 5-hydroxyindole-acetic acid by 22%. Other monoamines, their metabolites or metabolite/monoamine ratios were not affected. We conclude that desipramine given systemically at infancy reduces dorsal striatal metabolism of serotonin at adolescence in the rat.

Animals↗

PubMed1999

Antinociceptive effects induced by desipramine and fluoxetine are dissociated from their antidepressant or anxiolytic action in mice.

This study aimed to evaluate the relationship between some aspects of experimental depression, anxiety and the antinociceptive effects of fluoxetine and desipramine in mice. Acute administration of fluoxetine and desipramine (5, 10 and 20 mg/kg, i.p.) showed significant antinociceptive effects in the hot-plate test and against the early and late phase of the mouse formalin test, dissociated from its antidepressant and anxiolytic effects as measured in the forced swimming and in the plus-maze tests, respectively. Neither fluoxetine nor desipramine, at the doses tested, produced significant effects on locomotor activity. Furthermore, both compounds were ineffective in the tail-flick phasic model of nociception. In conclusion, the results suggest that without the distinction of serotonergic and noradrenergic contributions, the acute antinociceptive effects of fluoxetine and desipramine in mice are independent of their sedative, antidepressant and anti-anxiety properties.

Journal Article↗

PubMed1989

Neuroanatomically selective down-regulation of beta adrenergic receptors by chronic imipramine treatment: relationships to the topography of [3H]imipramine and [3H] desipramine binding sites.

The down-regulation of beta adrenergic receptors by chronic imipramine treatment was investigated with high resolution autoradiography of [125I]pindolol binding to brain sections. Neuroanatomically selective down-regulation of [125I]pindolol binding was found after chronic imipramine treatment. Subdivisions of the amygdala and hippocampus and discrete cortical regions were differentially affected. In the hippocampus, reduction of [125I]pindolol binding was observed in imipramine-treated rats in the CA-1 stratum radiatum and dentate molecular layer, but not in the CA-3 stratum radiatum. In the amygdala, the basolateral nucleus exhibited reduced [125I]pindolol binding after imipramine treatment but the central and medial nuclei were not affected. Chronic imipramine treatment was also associated with reduced [125I]pindolol binding in layer 1 of the cingulate cortex and layer 3 of the piriform cortex. In contrast, no effect on [125I]pindolol binding was apparent in the ventrolateral thalamic nucleus, caudate-putamen, lateral hypothalamus or layers 2 and 3 of the somatosensory cortex. In order to determine if regional variation in binding sites for imipramine, or its pharmacologically active metabolite desipramine, was responsible for the observed neuroanatomically selective reduction in [125I]pindolol binding, the binding of [3H]imipramine and [3H]desipramine was investigated. In some brain regions that exhibited high densities of [3H]imipramine and [3H]desipramine binding sites, [125I]pindolol binding was reduced after chronic treatment with imipramine. However, other regions that contained high densities of binding sites for antidepressant drugs did not show a reduction in [125I]pindolol binding after chronic imipramine treatment. Thus, regional binding of [3H]imipramine or [3H]desipramine cannot fully explain the neuroanatomical specificity of imipramine-induced beta adrenergic receptor down-regulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Efficacy of desipramine in depressed outpatients. Response according to research diagnosis criteria diagnoses and severity of illness.

The efficacy of desipramine for mild depression was tested in a double-blind, placebo-controlled study of outpatients with scores below 19 on the Hamilton Rating Scale for Depression (HAM-D). Of 103 such patients, 23 dropped out and 16 improved during a ten-day placebo period. Among 64 patients completing the randomized portion of the study, significantly more improved with desipramine that with placebo. The Research Diagnostic Criteria (RDC) category of major depressive disorder largely accounted for the drug-placebo response difference found for the entire sample. Patients with intermittent depressive disorder improved significantly less frequently with desipramine than patients with major depressive disorder. Independent of RDC diagnosis, severity of illness correlated with outcome. Thus, patients with pretreatment HAM-D scores at or above the median demonstrated significant drug effect, while patients with lower pretreatment HAM-D scores did not.

Adolescent↗

PubMed1989

Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison.

Forty-eight children and adolescents with severe primary obsessive-compulsive disorder completed a 10-week double-blind crossover trial of clomipramine hydrochloride (mean dose [+/- SD], 150 +/- 53 mg/d) and desipramine hydrochloride (mean dose [+/- SD], 153 +/- 55 mg/d). Clomipramine was clearly superior to desipramine in significantly reducing obsessive-compulsive symptoms. Age at onset, duration and severity of illness, type of symptom, and plasma drug concentrations did not predict clinical response to clomipramine. Sixty-four percent of patients who received clomipramine as their first active treatment showed at least some sign of relapse during desipramine treatment. We further document the specificity of the antiobsessional effect of clomipramine and the need for maintenance treatment.

Adolescent↗

PubMed1977

Impurities in drugs I: Imipramine, desipramine, and their formulations.

Nineteen lots of imipramine tablets and four lots of desipramine tablets were examined for impurities by TLC. Iminodibenzyl, desipramine, and 10,11-dihydro-5-[3-(methylamino-3'-dimethylaminopropyl)propyl]-5H-dibenz[b,f]azepine dihydrobromide (I) were found in some imipramine tablets, and iminodibenzyl and imipramine were found in some desipramine tablets, all at levels of less than 0.3% of label claim of the drug. Except for I, the identity of the impurities was established by comparison with known standards; I was synthesized and its composition was established by elemental analysis. All impurities, including I, were characterized by TLC, GLC, and mass spectrometry.

Capsules↗

PubMed1982

GLC method for iminodibenzyl and desipramine impurities in imipramine hydrochloride and its formulated products.

A GLC method is described for the determination of iminodibenzyl and desipramine impurities in imipramine hydrochloride and its formulated products. These impurities were extracted from an alkaline solution with a mixture of 30% methylene chloride in hexane for chromatography on a 3% OV-17 GLC column. Iminodibenzyl was determined using anthracene as an internal standard and desipramine was determined (after derivatization) using nortriptyline as an internal standard. Based on spiked excipient mixtures typically used to compound imipramine tablets, recoveries were 93-109% for iminodibenzyl and 93-107% for desipramine at 0.2-0.4% of the labeled claim of imipramine. Minimum detection levels were approximately 0.02% for each impurity, and procedural standards gave coefficients of variation of less than 1% for each impurity. The method was linear in the 0.05-0.5 microgram range and typically gave correlation coefficients greater than or equal to 0.999.

Amines↗

PubMed1986

Acute versus repeated administration of desipramine in rats and mice: relationships between brain concentrations and reduction of immobility in the swimming test.

Immobility scores in the swimming test and brain concentrations of desipramine were determined in rats and mice following repeated injection of the antidepressant versus acute administration of either a behaviorally effective or ineffective dose of the drug. Five injections (IP) of desipramine (each injection being performed at the measured T1/2 of the drug in the brain) reduced immobility scores by 30%, whereas this regimen resulted in brain drug concentrations not different from those obtained after a single, behaviorally ineffective dose of desipramine. It is suggested that the enhanced "antidepressant" response such as that frequently observed in animals after repeated injection of imipramine-like drugs does not involve accumulation of the drug in the brain.

Animals↗

PubMed1989

Inhibition of neuronal noradrenaline transport (uptake1) and desipramine binding by amiloride and ethylisopropylamiloride.

The diuretic amiloride and its N-5 substituted analogue ethylisopropylamiloride (EIPA) inhibit both the specific high affinity desipramine binding to isolated plasma membranes of PC12 rat phaeochromocytoma cells and the carrier-mediated neuronal uptake of noradrenaline into PC12 cells. The inhibition by EIPA of both desipramine binding (Ki = 5.6 mumol/l) and noradrenaline uptake (Ki = 24 mumol/l) inversely depend on the extracellular sodium concentration. The degree of inhibition increased with decreasing sodium concentration. A more detailed analysis of the mode of interaction revealed a competitive interaction between EIPA and desipramine binding but an "uncompetitive" interaction between EIPA and noradrenaline uptake. EIPA is the first inhibitor of uptake1 known so far, which reduces both Km and Vmax of neuronal noradrenaline transport. Extracellular alkalinization from pH 7.4 to 7.9 during incubation with EIPA markedly increased the effects on the kinetics of noradrenaline transport. A model has been proposed to explain the kinetic phenomena. It is based on the hypothesis that EIPA diffuses through the plasma membrane and binds to the inward facing sodium binding site of the neuronal noradrenaline carrier.

Amiloride↗

PubMed1988

Is phosphodiesterase inhibition a new mechanism of antidepressant action? A double blind double-dummy study between rolipram and desipramine in hospitalized major and/or endogenous depressives.

Unlike conventional antidepressants, rolipram (a new approach in the treatment of depression) stimulates both the presynaptic and the postsynaptic component of monoaminergic transmission. Several double blind trials are under way to assess the clinical efficacy and safety of this compound. The present study was a randomized, 4-week interindividual double blind double-dummy comparison with desipramine in inpatients with major (DSM-III) and/or endogenous (ICD-9) depressions. After a minimum washout period of three days the patients received either 0.50 mg rolipram or 25 mg desipramine orally t.i.d. for the first three days, then 0.75 mg rolipram or 50 mg desipramine t.i.d. until day 28. Rating tests were based principally on the AMDP-system and the HAMD scale. The study showed no differences between the two drugs as regards the efficacy, but a definite trend in favour of rolipram as regards the side effects and, in particular, anticholinergic effects.

Adolescent↗

PubMed1984

Effects of desipramine, trifluoperazine and other inhibitors of calmodulin on the secretion of catecholamines from the adrenal medulla and postganglionic sympathetic nerves of the salivary gland.

The effects of various drugs, known to be inhibitors of calmodulin, were tested on the secretion of catecholamines (CA) from the adrenal medulla and sympathetic nerves of the salivary gland of the rat. Secretion of CA from the perfused adrenal gland was evoked by injection of acetylcholine (ACh, 50 micrograms), excess K (700 micrograms), or transmural stimulation of splanchnic nerves (300 pulses at 10 Hz). Release of 3H-noradrenaline in the perfused salivary gland was evoked by transmural stimulation at 3 Hz for 30 s. CA secretion was reduced in a dose-dependent manner by 0.3 microM to 10 microM desipramine or imipramine. The effect of low doses (0.3 microM) was more pronounced on the secretion evoked by ACh and splanchnic nerve stimulation than that by excess K. The inhibition was independent of the frequency of nerve stimulation. Trifluoperazine (10-100 microM) and chlorpromazine (10-100 microM) reduced CA secretion evoked by all of the three procedures. The inhibitory effects of desipramine, trifluoperazine and chlorpromazine were completely reversed within 1 h after their washout. Secretion of CA obtained after reintroduction of Ca to the adrenal gland previously perfused with Ca-free medium was not blocked by desipramine or trifluoperazine. In fact, these agents markedly enhanced the secretory response. None of the drugs enhanced spontaneous secretion of CA from the adrenal gland during the nonstimulation period. Adrenal medullary cells accumulated significant amounts of Ca45 (0.88 pg/mg) after stimulation with ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1986

Spinal facilitation in cholinergic-sympathetic efferents by desipramine.

Electrodermal potentials (EDPs) evoked by electrical stimulation of the cholinergic-sympathetic system at different levels were recorded in the forepaws of anaesthetized cats and used as a measure of sudomotor activity. After pretreatment with yohimbine (0.25 mg/kg i.v.) to block alpha 2-adrenoceptors, unilateral electrical stimulation of the hypothalamus (square wave pulses 1 ms duration, 16 Hz, 2 s train length at intervals of 1 min) induced EDPs in both forepaws. Injection of the inhibitor of neuronal catecholamine reuptake, desipramine (1 mg/kg i.v.), facilitated the EDPs in both forepaws, even though access of the drug to the sweat glands was prevented by application of a tourniquet to one paw. The facilitation was abolished by injection of the specific alpha 1-adrenoceptor antagonist, prazosin (0.5 mg/kg i.v.). An equal enhancement of this effect by desipramine (1 mg/kg i.v.) and its abolition by prazosin (0.5 mg/kg i.v.) was obtained in cats with the brain stem transected at the level of the medulla oblongata and electrical stimulation of the spinal cord at C1. EDPs evoked in the right forepaw by preganglionic electrical stimulation of the right stellate ganglion were inhibited by desipramine (1 mg/kg i.v.). From these and previous results it is concluded that inhibition of neuronal reuptake of catecholamines results in facilitation of activity in sudomotor efferents. This effect is mediated by spinal alpha 1-adrenoceptors and provides an explanation of the occasional occurrence of excessive sweating in psychiatric patients treated with tricyclic antidepressants.

Animals↗

PubMed1989

Lack of effect of chronic desipramine treatment on dopaminergic activity in the nucleus accumbens of the rat.

The binding of [3H]SCH 23390 to dopamine (DA) D1-receptors was measured in the nucleus accumbens of rats treated chronically with desipramine for 14 days. DA D1- and D2-receptor binding using [3H]SCH 23390 and [3H]spiperone, respectively as ligands, was determined in rats treated for 28 days. Neither Bmax nor Kd values were influenced by chronic desipramine treatment. In addition, chronic desipramine treatment (28 days) did not influence the dose dependent, quinpirole (10-1000 nM)-mediated inhibition of the electrically stimulated release of [3H]DA release and [14C]ACh from nucleus accumbens slices or the dose dependent increase in [3H]DA release and decrease in [14C]ACh release in the presence of 1 and 10 microM nomifensine. Therefore, our results suggest that the effect of chronic antidepressant treatment cannot be attributed to changes in either DA D1- or D2-receptor binding or DA D2-receptor function in the nucleus accumbens.

Acetylcholine↗