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PubMed1980

Electrocardiogram changes and plasma desipramine levels during treatment of depression.

Twenty-six symptomatic subjects who met research diagnostic criteria for major affective disorder and were free of cardiovascular disease were treated for 3 wk with a fixed dosage schedule of desipramine (DMI) to a maximum of 200 mg/day. An electrocardiogram (ECG) and DMI plasma level determinations were obtained before treatment and weekly thereafter. DMI levels during the trial ranged from 13.4 to 882.2 ng/ml. DMI treatment was associated with increase in heart rate (p less than 0.001), prolongation of the PR (p less than 0.001), QRS (p less than 0.001), and QTc intervals (p less than 0.001), and increase in T wave amplitude (p less than 0.001). Significant (p less than 0.001) but relatively weak correlations were noted between DMI plasma levels and heart rate (r = 0.405), QRS interval (r = 0.346), QTc interval (r = 0.534), and T wave amplitude (r = -0.386). PR interval prolongation was independent of DMI levels (r = 0.171). DMI treatment induced no clinically significant ECG alterations or cardiovascular adverse effects. The relevance of DMI plasma level and the possible roles of other contributing factors in the production of these ECG changes are discussed.

Adult↗
PubMed1982

Active metabolites of imipramine and desipramine in man.

Active hydroxy metabolites of imipramine (IMI) and desipramine (DMI) have been quantified in plasma and cerebrospinal fluid (CSF) from patients at steady-state. In plasma of prepubescent boys and adults the concentration of unconjugated 2-hydroxyimipramine is only 15% to 25% that of IMI; 2-hydroxydesipramine (OH-DMI) concentration, however, is usually 50% that of DMI and in some cases OH-DMI is the predominant compound. In CSF from adult patients the ratio of concentrations of OH-DMI/DMI is higher than in plasma. Judging from the CSF/plasma ratio 12% of DMI exists in the free form at steady state, whereas 16% of OH-DMI is free (P less than 0.02). There is no evidence for saturation of hydroxylation within the therapeutic dose and concentration ranges investigated. On the basis of a steady-state OH-DMI/DMI ratio of less than 1/30 in plasma 5% of the population studied could be classified as deficient DMI hydroxylators. This in the same as the incidence of deficient debrisoquine hydroxylators reported in other populations.

Adolescent↗
PubMed1983

Desipramine hydroxylation: variability and effect of antipsychotic drugs.

Steady-state plasma concentrations of desipramine (DMI), unconjugated 2-OH DMI, and total 2-OH DMI were measured in 82 depressed inpatients, 35 of whom were concurrently receiving a phenothiazine or butyrophenone antipsychotic drug. In the patients not on an antipsychotic, the ratio of unconjugated metabolite to parent varied from 0.01 to 1.5, with a median of 0.48, and was inversely related to the parent drug level. Antipsychotic drug was associated with higher DMI levels and a lower proportion of OH-metabolite (median, 0.23). In both groups the unconjugated form accounted for only about 10% of the total metabolite. No relationship of age, sex, drinking history, or smoking to DMI or 2-OH DMI levels was found.

Adult↗
PubMed1984

The nonlinear kinetics of desipramine and 2-hydroxydesipramine in plasma.

Plasma levels of desipramine (DMI) and the unconjugated form of its principal metabolite 2-hydroxydesipramine (OH-D) were measured under steady-state conditions in nine depressed inpatients during treatment with 75 mg DMI every 12 hr and after at least 1 wk of an increased dose of DMI (after steady state). When DMI dosage was raised after an initial steady state had been reached, the rise in plasma DMI level was proportionately greater than the increase in dosage, suggesting saturation of DMI elimination pathways. Levels of OH-D rose in proportion to dose, suggesting saturation of DMI elimination by 2-hydroxylation could not explain DMI plasma level changes. In contrast, there were no dose-dependent effects on the disposition of amitriptyline or its metabolite nortriptyline in subjects receiving the same amitriptyline dose.

Administration, Oral↗
PubMed1986

Treatment of childhood hyperactivity with desipramine: plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response.

Twenty-nine boys with attention deficit disorder/hyperactivity were randomly assigned to receive desipramine (DMI; n = 17) or placebo (n = 12) for 14 days in a noncrossover, double-blind study. There was immediate behavioral improvement with DMI at day 3 that was sustained for 2 weeks; behavioral improvement did not correlate with plasma concentrations of DMI, hydroxy-DMI, or their sum at either days 3 or 14. There were no untoward side effects; there was a drug-induced increase in pulse and diastolic blood pressure. During drug therapy, the urinary excretion of norepinephrine, vanillymandelic acid, and 3-methoxy-4-hydroxyphenylglycol (MHPG) was decreased at both days 3 and 14. The plasma MHPG level was decreased at days 3 and 14 and (standing) plasma NE levels increased at day 14. The decreases in both urinary and plasma MHPG levels showed significant correlations with behavioral improvement during the second week. These data corroborate previous findings on sympathomimetic effects of tricyclic antidepressants in children and support a noradrenergic mechanism in the mediation of drug effects on attention deficit disorder/hyperactivity.

Administration, Oral↗
PubMed1988

Inhibition of desipramine 2-hydroxylation by quinidine and quinine.

Urinary excretion of desipramine (DMI) and 2-hydroxydesipramine (2-OH-DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2-OH-DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2-OH-DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2-OH-DMI. At similar does the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2-hydroxylation.

Adult↗
PubMed2003

Impact of maternal deprivation on brain corticotropin-releasing hormone circuits: prevention of CRH receptor-2 mRNA changes by desipramine treatment.

Corticotropin-releasing hormone (CRH) acts within the brain and pituitary to coordinate the overall endocrinological and behavioral stress response. From postnatal day (PND) 4 to 14, the infant rat displays minimal adrenal response to mild stress. However, maternal deprivation alters the pituitary-adrenal system such that the infants become responsive to specific stimuli. We hypothesized that maternal deprivation would also affect CRH brain circuits. Since tricyclic antidepressants have been shown to decrease the adrenal response to stress in adult rats, we hypothesized that CRH-related changes induced by maternal deprivation would be prevented by this treatment. Thus, we investigated CRH-related molecules on animals that were maternally deprived on PND 13 compared with nondeprived animals. We found that maternal deprivation caused alterations in the gene expression of both CRH receptors (CRHr) 1 and 2 in specific brain regions, and that some of these effects were augmented by chronic isotonic saline injections. There was a significant increase in CRH, CRHr1, and r2 mRNA in the cortex. In amygdala, CRHr1 and r2 mRNAs were decreased. CRHr2 mRNA was also decreased in the ventromedial nucleus of the hypothalamus, whereas an increase was detected in the hippocampal pyramidal cells. One week of desipramine (DES) administration preceding the maternal deprivation event prevented all the deprivation-induced changes in CRHr2 mRNA, regardless of the direction of the original change. We also found that chronic injection treatments enhanced the adrenocortical response and improved the efficiency of negative feedback in maternal deprivation animals. These results demonstrate that maternal deprivation elicits modifications of CRH brain circuits in a site-specific manner, and that the regulation of CRHr2 gene expression is mediated by mechanisms different from those involved with the modulation of CRHr1 in the infant rat.

Animals↗
PubMed2006

Chronic treatment with desipramine improves cognitive performance of rats in an attentional set-shifting test.

Alterations in central monoaminergic neurotransmission are important in the actions of many antidepressants. This study tested the hypothesis that tonic elevation of noradrenergic (NA) neurotransmission in medial prefrontal cortex (mPFC) by chronic treatment with the selective norepinephrine (NE) reuptake blocker desipramine (DMI) may contribute to the beneficial cognitive effects of this antidepressant drug (AD). Male Sprague-Dawley rats were treated with DMI acutely (15 mg/kg, i.p.) or chronically for 21 days (7.5 mg/kg/day via osmotic minipump) before assessing performance on an attentional set-shifting test. The extradimensional set-shifting component of this test reflects a process of cognitive flexibility that is dependent upon mPFC, and that we have shown previously to be facilitated by NA activity in mPFC. Microdialysis was performed to measure NE release in mPFC concurrently with behavioral testing. Acute DMI treatment produced an increase in extracellular NE levels in mPFC, and a modest improvement in overall performance across all task stages of the attentional set-shifting test, but failed to produce a significant improvement in any of the individual specific tasks comprising the test sequence. Chronic DMI treatment tonically elevated basal extracellular NE levels in mPFC, associated with a significant improvement in performance specifically on the extradimensional set-shifting component of the test. There was also a significant reduction in set loss errors in rats treated chronically with DMI. Hence, tonic elevation of NA transmission in mPFC by chronic DMI treatment was associated with a time-dependent facilitation of cognitive flexibility that may contribute to the mechanism whereby chronic treatment with ADs, specifically NE reuptake blockers, may exert a beneficial therapeutic effect on cognition in depressed patients.

Adrenergic Uptake Inhibitors↗
PubMed2003

Effects of reducing contingency management values on heroin and cocaine use for buprenorphine- and desipramine-treated patients.

AIMS: During 3 months where contingency management (CM) had an escalating value for each consecutive drug-free urine (escalating CM), cocaine- and heroin-abusing patients significantly increased drug-free urines. The 'escalating CM' was eliminated during months 4-6 to assess any reduction in drug-free urines. DESIGN: Patients who completed a 3-month, randomized, double-blind, trial evaluating CM versus non-CM and desipramine (DMI) versus placebo, had an 'escalating CM' eliminated during months 4-6. The CM and non-CM groups were compared using thrice-weekly urine samples. SETTING: Out-patient buprenorphine maintenance for 6 months. PARTICIPANTS: All 75 of the 160 original study patients who completed month 3 of the clinical trial. INTERVENTION: The 'escalating CM' was eliminated for all 3 months and during months 5 and 6 the response requirement was also increased to two and then three consecutive drug-free urines in order to obtain a voucher. MEASUREMENTS: Urine toxicology for opiates and cocaine. FINDINGS: After eliminating the 'escalating CM', the CM group showed a decline in combined opioid- and cocaine-free urines. This decline within the CM group was greater in those treated with DMI than placebo. CONCLUSIONS: Buprenorphine with DMI maintained drug abstinence after eliminating the 'escalating CM', but not after increasing the response requirement, suggesting the need for more intensive psychosocial interventions during CM.

Adult↗
PubMed1994

5-Hydroxytryptamine2 and beta-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination.

A chronic (14-day) study was initiated to investigate the effects of combined fluoxetine (FLU) and desipramine (DMI) treatment on the densities and affinities of beta-adrenergic and 5-hydroxytryptamine2 (5-HT2) receptors. Male Sprague-Dawley rats were administered the following doses using osmotic minipumps: FLU, 10 mg/kg/day; DMI, 5, 10, or 15 mg/kg/day; FLU, 10 mg/kg/day, plus DMI, 5 mg/kg/day; or vehicle (distilled water). After 14 days the cortex was dissected out and used for [3H]-ketanserin (5-HT2) binding, [3H]CGP-12177 (beta-adrenergic) binding, and drug level analysis. All animals receiving DMI showed significant down-regulation of 5-HT2 receptors except those receiving FLU in combination. DMI down-regulated beta-adrenergic receptors in a dose-dependent manner, with significantly greater down-regulation seen with the combination than with DMI (5 mg/kg/day) alone. This latter effect was apparently the result of greater levels of DMI in cortex with the combination than with DMI (5 mg/kg/day) alone. FLU had no effect on 5-HT2 or beta-adrenergic receptors on its own. Coadministration of FLU and DMI resulted in a doubling of levels of FLU and its demethylated metabolite, norfluoxetine (NFLU), and a tripling of DMI levels compared with values observed when FLU (10 mg/kg/day) or DMI (5 mg/kg/day) was administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

NMDA receptor subtype selectivity: eliprodil, polyamine spider toxins, dextromethorphan, and desipramine selectively block NMDA-evoked striatal acetylcholine but not spermidine release.

NMDA receptor stimulation concomitantly increases the release of [14C]acetylcholine and [3H]-spermidine from rat striatal slices in vitro. The NMDA-induced release of both acetylcholine and spermidine was blocked with equal potency by the NMDA channel blocker phencyclidine (0.1-10 microM). However, certain other channel blockers, including dextromethorphan (1-100 microM), which antagonized NMDA-evoked acetylcholine release without affecting NMDA-evoked spermidine release, and dextrorphan (1-100 microM) and memantine (1-100 microM), which block NMDA-evoked acetylcholine release more potently than NMDA-evoked spermidine release, showed greater selectivity of action. As previously shown for ifenprodil, eliprodil (SL82.0715; 1-100 microM) blocked NMDA-evoked acetylcholine but not spermidine release. This selectivity is also observed for other agents interacting with the polyamine site(s) on the NMDA receptor, including arcaine (1-1,000 microM), philanthotoxin343, and argiotoxin636 (10 microM) and was also noted for desipramine (1-100 microM). The NMDA-induced release of acetylcholine and spermidine is likely to be mediated by different native NMDA receptor subtypes, and several NMDA antagonists may be candidates for a selective action at a particular NMDA receptor subtype.

Acetylcholine↗
PubMed1998

Somatodendritic alpha2-adrenoceptors in the locus coeruleus are involved in the in vivo modulation of cortical noradrenaline release by the antidepressant desipramine.

The effect of the antidepressant and selective noradrenaline reuptake blocker desipramine (DMI) on noradrenergic transmission was evaluated in vivo by dual-probe microdialysis. DMI (1, 3, and 10 mg/kg, i.p.) dose-dependently increased extracellular levels of noradrenaline (NA) in the locus coeruleus (LC) area. In the cingulate cortex (Cg), DMI (3 and 10 mg/kg, i.p.) also increased NA dialysate, but at the lowest dose (1 mg/kg, i.p.) it decreased NA levels. When the alpha2-adrenoceptor antagonist RX821002 (1 microM) was perfused in the LC, DMI (1 mg/kg, i.p.) no longer decreased but rather increased NA dialysate in the Cg. In electrophysiological experiments, DMI (1 mg/kg, i.p.) inhibited the firing activity of LC neurons by a mechanism reversed by RX821002. Local DMI (0.01-100 microM) into the LC increased concentration-dependently NA levels in the LC and simultaneously decreased NA levels in the Cg. This decrease was abolished by local RX821002 administration into the LC. The results demonstrate in vivo that DMI inhibits NA reuptake at somatodendritic and nerve terminal levels of noradrenergic cells. The increased NA dialysate in the LC inhibits noradrenergic activity, which in part counteracts the effects of DMI on the Cg. The modulation of cortical NA release by activity of DMI at the somatodendritic level is mediated through alpha2-adrenoceptors located in the LC.

Adrenergic alpha-Antagonists↗
PubMed2002

Effects of desipramine treatment on norepinephrine transporter gene expression in the cultured SK-N-BE(2)M17 cells and rat brain tissue.

The antidepressant desipramine (DMI) is a selective inhibitor of norepinephrine (NE) transport that down-regulates the norepinephrine transporter (NET) protein in a concentration- and time-dependent manner in vitro. In this study, possible regulatory effects of DMI on NET mRNA and protein levels were investigated with the NET-expressing SK-N-BE(2)M17 cell line and rat brain tissue. Northern blot analysis showed that incubation of the cultured cells with DMI (5-500 nm) for 3 days reduced levels of NET mRNA in both its 5.8-kb (by up to 58%) and 3.6-kb forms (to 68%), whereas incubation for 14 days increased both levels (to 40% and 100%) in a concentration-dependent manner. In contrast, NET protein levels decreased after 3-14 days of exposure of the cells to DMI, as determined by western blotting. The in vitro findings were supported by in vivo treatment of rats with DMI. Thus, in situ hybridization demonstrated initially decreased, and later increased, NET mRNA levels in locus coeruleus (LC) tissue of rats treated with DMI; whereas NET protein levels in the LC were reduced after 14 days, but unchanged after three daily DMI treatments. Thus, DMI had similar effects on NET expression in vitro and in vivo, with opposite changes in NET mRNA and protein levels, suggesting that the regulatory mechanisms involved are complex and non-congruent.

Animals↗
PubMed1986

Acute effects of desipramine and clomipramine on pituitary-adrenal axis in man.

Brain neurotransmitters play an essential role in central regulation of hypothalamic factors which stimulate or inhibit the secretion of pituitary hormones. Insight in this complex system might be obtained by analysing changes in pituitary and peripheral hormone secretion following the administration of neuroactive drugs which influence the action of neurotransmitters. Desipramine is well-known to inhibit presynaptic norepinephrine reuptake, clomipramine on the other hand interferes with the serotoninergic system. In 15 male volunteers, the effects of single-dose administration of each drug were studied in comparison to placebo. Basal concentrations of ACTH and cortisol, as well as the rise of both hormones following insulin-induced hypoglycemia, were studied. Basal cortisol values and the response to hypoglycemia were not affected by either pharmacon in this study. Slight differences could be seen in the ACTH responses, which were however not significant.

Adrenocorticotropic Hormone↗
PubMed1979

Chronic treatment with lithium or desipramine alters discharge frequency and norepinephrine responsiveness of cerebellar Purkinje cells.

Cerebellar Purkinje cells were studied by electrophysiological techniques in rats treated chronically with either desipramine (DMI) or lithium chloride given intragastrically. A striking decrement occurred in discharge frequencies of simple spikes and climbing fiber bursts in both groups of animals, similar to the depression produced by iontophoresis of these agents. Chronic treatment with DMI markedly decreased responsiveness to iontophoretically applied norepinephrine (NE), whereas long-term LiCl therapy slightly enhanced response to NE; responses to gamma-aminobutyric acid were unchanged by these treatments. The inhibitory responses to locus ceruleus stimulation were unaffected by chronic LiCl treatment. The effects of these chronic treatments on responsiveness to NE are opposite to the effects these same drugs produce when administered by acute iontophoresis to single cells: DMI then potentiates and LiCl antagonizes noradrenergic responses. These results provide electrophysiological evidence for reciprocal adaptive changes in NE sensitivity, supporting results of biochemical studies.

Animals↗
PubMed2003

chi-Conopeptide MrIA partially overlaps desipramine and cocaine binding sites on the human norepinephrine transporter.

The interactions of chi-conopeptide MrIA with the human norepinephrine transporter (hNET) were investigated by determining the effects of hNET point mutations on the inhibitory potency of MrIA. The mutants were produced by site-directed mutagenesis and expressed in COS-7 cells. The potency of MrIA was greater for inhibition of uptake by hNET of [3H]norepinephrine (Ki 1.89 microM) than [3H]dopamine (Ki 4.33 microM), and the human dopamine transporter and serotonin transporter were not inhibited by MrIA (to 7 microM). Of 18 mutations where hNET amino acid residues were exchanged with those of the human dopamine transporter, MrIA had increased potency for inhibition of [3H]norepinephrine uptake for three mutations (in predicted extracellular loops 3 and 4 and transmembrane domain (TMD) 8) and decreased potency for one mutation (in TMD6 and intracellular loop (IL) 3). Of the 12 additional mutations in TMDs 2, 4, 5, and 11 and IL1, three mutations (in TMD2 and IL1) had reduced MrIA inhibitory potency. All of the other mutations tested had no influence on MrIA potency. A comparison of the results with previous data for desipramine and cocaine inhibition of norepinephrine uptake by the mutant hNETs reveals that MrIA binding to hNET occurs at a site that is distinct from but overlaps with the binding sites for tricyclic antidepressants and cocaine.

Amino Acid Sequence↗
PubMedDate not supplied

Desipramine treatment for cocaine dependence in buprenorphine- or methadone-treated patients: baseline urine results as predictor of response.

The prognostic importance of baseline urines for cocaine was examined in a randomized, placebo-controlled, twelve-week clinical trial in 165 opioid- and cocaine-dependent patients who were treated with desipramine (DMI) in combination with buprenorphine (BUP) or methadone (Meth). Patients with a cocaine-positive urine at baseline (CU+) had significantly fewer cocaine-free urines than those with a negative urine at baseline (CU-neg). The CU+ patients showed a treatment effect of DMI. This DMI effect was significant in patients maintained on BUP but not on Meth.

Adrenergic Uptake Inhibitors↗
PubMedDate not supplied

A fatal intoxication involving carbamazepine, desipramine, and ethylene glycol.

A fatal intoxication involving multiple substances including carbamazepine (CBZ), desipramine (DI), and ethylene glycol (EG), in which the blood CBZ concentration was higher than any previously reported in the literature is presented. Each compound, as well as the 10,11-epoxide metabolite of carbamazepine (CBZ-EP), was quantified in blood (CBZ, 79 mg/L; CBZ-EP, 11 mg/L; DI, 4.2 mg/L; EG, 3.6 g/L), bile (CBZ, 69 mg/L; CBZ-EP, 13 mg/L; DI, 23 mg/L; EG, 4.8 g/L), urine (CBZ, 6.5 mg/L; CBZ-EP, 5.7 mg/L; DI, 30 mg/L; EG, 3.3 g/L), stomach contents (CBZ, 280 mg; DI, 49 mg; EG, 2.8 g), liver (CBZ, 75 mg/kg; CBZ-EP, 11 mg/kg; DI, 49 mg/kg; EG, 2.0 g/kg), and kidney (CBZ, 41 mg/kg; CBZ-EP, 11 mg/kg; DI, 23 mg/kg; EG, 1.9 g/kg) using the following analytical techniques: high performance liquid chromatography with ultraviolet detection for CBZ and CBZ-EP, gas-liquid chromatography with mass selective detection for DI and gas-liquid chromatography with flame ionization detection for EG.

Adult↗