Drugs Desipramine Research Articles

Sudden Death in Children Treated with a Tricyclic Antidepressant

In its June 1st issue , The Medical Letter on Drugs and Therapeutics (1990) reported on three cases of sudden death 8to 9-year-old children during routine treatment with the tricyclic antidepress ant (TCA) drug desipramine (DMI) (Norpramin, Pertofrane'>, generic) ove r an uncert ain period of time. The first case of sudden death , which has been included the new Norpramin' labeling, occurred an 8-year-old boy, without known cardi ac disease , treated with unknown doses of the drug for 2 years for attent ion deficit hyperactivity disorder (ADHD). The second case was that of an 8-ye ar-old boy treat ed for attention deficit disorder with 50 mg/d of DMI for 6 months , and the third one was a 9-year-old boy treated with DMI with unknown doses and for an unknown time. Plasma levels of DMI obtained postarrest from all three children were reportedly in the therapeutic or subtherapeutic range The tragic deaths of these children are presumed to have occurred secondary to cardiac abnormalities . However , the limited information available leaves many unan swe red questions . It is unclear if these patients had a recent dose increase , a preexisting medical or cardi ac abnormality, or whether they were adequately monitored. For example, while there is not much more additional information available, Merrel Dow ' s records indicated that the second child had a muscle biopsy performed 4 yea rs before this child's death that showed nondefined skel etal muscle abnormality . It is also noted that paroxysmal atr ial tachycardia was obse rved durin g the biopsy procedure and that that child had a famil y history of sudden cardiac death. Thus, the causal relationship between DMI and these children ' s deaths is uncle ar , and the impli cations for the use of TCAs the pediatric age group remains ambiguous . TCAs, mainly imipramine, have been used the treatment of several childhood psychiatric disorders over the last 3 decades. With stimulants and ant ipsychotics , they represent the mainstay of pediatric psychopharmacology. In pediatric psychiatry , TCAs have been used the treatment

Effects of chronic treatments with amineptine and despiramine on motor responses involving dopaminergic systems

The acute effects of increasing doses of the antidepressant drugs amineptine (5-40 mg/kg, IP) and desipramine (5-20 mg/kg IP) were studied in mice on three parameters of the activity (the horizontal activity, the vertical activity and the number of small movements without displacement) measured in a computerized Digiscan actimeter. The horizontal and vertical activities were dose dependently and similarly increased by acute amineptine, whereas the number of movements without displacement was increased up to 10 mg/kg with no further significant modification up to 40 mg/kg; in contrast, all three parameters were reduced in an identical manner by desipramine. The changes in the responses to the selective D-1 dopamine (DA) receptor agonist SK&F 38393 (1.87-30 mg/kg, SC), to the selective D-2 DA receptor agonist LY 171555 (0.1-1.6 mg/kg, SC) and to the selective DA uptake inhibitor GBR 12783 (1.25-20 mg/kg, IP) were measured on the three parameters of activity in mice chronically treated with amineptine (20 mg/kg, IP twice daily during 15 days) or by desipramine (10 mg/kg, IP, twice daily during 15 days). The chronic treatments with amineptine or desipramine did not modify the motor stimulant effects GBR 12783 and of SK&F 38393 on the three parameters (excepted for a slight modification of the horizontal activity for 7.5 mg/kg SK&F 38393 in mice chronically treated with amineptine). In contrast, the motor inhibitory effects of the lowest doses of LY 171555 (0.1-0.4 mg/kg) were strongly reduced in mice chronically treated with amineptine or desipramine but only on the horizontal activity with no change on the vertical activity and on the number of small movements without displacement.(ABSTRACT TRUNCATED AT 250 WORDS)

Single and multiple desipramine exposures of cultured cells: Changes in cellular anisotropy and in lipid composition of whole cells and of plasma membranes

Effects of the antidepressant drug desipramine (DMI) on fluorescence anisotropy were studied in living cultured human fibroblasts, rat brain astrocytes and rat ROC-1 hybridoma cells (oligodendrocytes × C6). Fluorescence anisotropy, a measure for fluidity, was measured by means of a fluorescence polarization technique using a set of n-(9-anthroyloxy) fatty acids as markers. Apparent fluorescence anisotropies were determined in cells following single or multiple dose exposures to 5 μm DMI at 37° and compared to control cells. In all three cell types single doses of DMI led to significant decreases in anisotropies of the deeper layers (12-AS) of the membranes only, suggesting increases in fluidity. Repeated exposures to 5 μM DMI led to cell specific, significant changes in anisotropies of the superficial membrane layers, as determined by 2-AP, 6-, 7- and 9-AS. The resulting anisotropy values of the three different cell types became more alike than prior to DMI exposure. Alterations in anisotropies were accompanied with changes in the phospholipid patterns of whole cells and isolated plasma membrane vesicles. The changes of PC/PE ratios were consistent with changes observed in fluorescence anisotropies. Such alterations may be individual regulatory responses of the cells to the chronic presence of the drug within the membranes.

A Double-Blind Placebo Controlled Study of Desipramine in the Treatment of ADD: I. Efficacy

The tricyclic antidepressant drug desipramine (DMI) was evaluated in the treatment of young patients with attention deficit disorder with hyperactivity (ADDH) in an unselected sample of 62 clinically referred patients, 43 (69%) of whom previously responded poorly to psychostimulant treatment. The 42 children and 20 adolescents were assigned randomly to receive DMI (N = 31) or placebo (N = 31) for up to 6 weeks in a parallel groups, double-blind study. Clinically and statistically significant differences in behavioral improvement were found for DMI over placebo, at an average (+/- SEM) maximal daily dose of 4.6 +/- 0.2 mg/kg; 68% of DMI-treated patients were considered very much or much improved, compared with only 10% of placebo patients (p less than 0.001). DMI was well tolerated, even at the relatively high doses used. These findings suggest that DMI can be an effective treatment in the management of pediatric patients with ADDH, including patients who failed to respond to stimulants.

Organspecific, qualitative changes in the phospholipid composition of rats after chronic administration of the antidepressant drug desipramine

Rats were chronically treated with daily i.p. injections of 10 mg/kg desipramine for 21 days. A 30% decrease in the number of β-adrenoceptors was observed in brain. A receptor desensitization of similar extent was noted in submaxillary glands and lung. No change in β-adrenoceptor number was present in heart. Total phospholipid contents were not altered in these organs after chronic drug treatment. However, organ-specific changes were found in the phospholipid composition of submaxillary glands, lung and liver but not in whole brain and heart. The changes were variable but an increase in phosphatidylinositol and decreases in phosphatidylethanolamine and sphingomyelin were consistent. Possible alterations in the phospholipid composition of the brain might have been masked by the large and stable pool of myelin phospholipids. A causal relationship between changes in the phospholipid composition and β-adrenoceptor desensitization is discussed.

Chronic treatment with antidepressant drugs and ECT differentially modifies the hypothermic action of clonidine and guanfacine.

The hypothermia inducing action of clonidine and guanfacine was abolished by yohimbine and idazoxan pretreatment which suggests an alpha 2-adrenoceptor involvement in this effect. The effects of acute and chronic treatment with the antidepressant drugs desipramine (DMI), amitriptyline (AMI), maprotiline (MAP), mianserin (MIAN), iprindol (IPR), alaproclate (ALA) and electroconvulsive treatment (ECT) on the hypothermic action of the alpha 2-adrenoceptor agonists clonidine and guanfacine were studied. Acute administration of MIAN potentiated clonidine induced hypothermia whereas acute MIAN, IPR and ALA potentiated guanfacine induced hypothermia. Repetitive DMI, AMI and MAP treatment attenuated clonidine-induced hypothermia whereas guanfacine-induced hypothermia was potentiated by chronic treatment with DMI, AMI, MAP and MIAN, ECT applied without anaesthesia attenuated both clonidine and guanfacine hypothermia, however, under ethyl ether anaesthesia ECT was effective only towards guanfacine hypothermia. This discrepancy is discussed in terms of the relative selectivity of the agonists used, the reliability of agonist studies for indexing receptor function, and possible pharmacokinetic interaction.

Subcellular distribution of the antidepressant drug desipramine in cultured human fibroblasts after chronic administration: Drug-effect on the subcellular distribution of accumulated phospholipids

Desipramine (DMI) is an important antidepressant drug and a lysosomotropic substance. In cultured fibroblasts it interferes with lysosomal functions, e.g. phospholipid degradation. Chronic exposure of cells with DMI induces storage of phospholipids. Subcellular fractionations of cultured human fibroblasts that had been exposed to a short pulse of 3H-DMI showed accumulation of DMI in two acidic compartments, one of high density represented the lysosomes and one of much lower density may contain pinosomes. In chronically exposed cells DMI accumulated in the subcellular fractions of lower density only. DMI induced an important shift of lysosomal enzymes from vesicles of high density to the ones of lower density. Phospholipids were accumulating in those vesicles of lower density as well as in the fractions that contained plasma membranes. DMI also accumulated in one part of the Golgi vesicles of acute and chronically exposed cells. In the latter phospholipids and arylsulfatase A activity were also accumulating. DMI possibly interferes with membrane recycling. This eventually could induce changes in phospholipid content and composition in the plasma membrane which may have important implications for membrane functions.

Opioid receptors in the brain of the rat following chronic treatment with desipramine and electroconvulsive shock

The effect of chronic administration of electroconvulsive shock and the antidepressant drug desipramine on binding to opioid receptors was studied in the cerebral cortex, the basal ganglia and the hippocampus of the forebrain of the rat. In vitro, desipramine inhibited the binding of enkephalinamide to opioid receptors through a reduction in the number of binding sites, whereas the affinity was unchanged or only slightly decreased. In vivo desipramine, injected daily (10 mg/kg) for three weeks, did not change the number of opioid binding sites in the forebrain of the rat. Chronic electroconvulsive shock, given twice a week for three weeks, had no effect on the number of opioid binding sites in the forebrain of the rat. The data do not support the hypothesis of shared effects of lithium, tricyclic antidepressants and electroconvulsive shock on the opiod peptide-opioid receptor systems.

Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors

The effects of the antidepressant drug desipramine (DMI) on the density of beta-drenoceptor sites were studied on intact cultured human cells: skin fibroblasts, lung fibroblasts and macrophages. Direct binding studies were performed with the radioligand 3H-CGP 12177, a hydrophilic beta-adrenergic antagonist. The confluent cell cultures were exposed to DMI and all three cell types showed a dose-dependent decrease in the number of beta-adrenergic binding sites. This receptor desensitisation was only seen after chronic exposure of the cells to DMI. The extent of desensitisation was comparable to that seen in brain following chronic treatment of rats with DMI. The affinity of the binding sites to the radioligand was not affected by the antidepressant drug action. From these results we suggest that the in vivo effect of antidepressant drugs on postsynaptic beta-adrenoceptor density, at least in part, reflects a primary drug action and not only an adaptive change to presynaptic events.

Studies on the Role of α2‐Adrenoceptors in the Control of Synaptosomal [3H]5‐Hydroxytryptamine Release: Effects of Antidepressant Drugs

The sensitivity of alpha 2-adrenoceptors on 5-hydroxytryptamine (5-HT) nerve endings obtained from rat cerebral cortex was investigated following treatment with the antidepressant drugs desipramine (10 mg/kg/day for 21-28 days) or clorgyline (1 mg/kg/day for 21-28 days). [3H]5-HT (100 nM) was used to load cortical synaptosomes (P2) after experiments with uptake inhibitors confirmed that this concentration of amine ensured exclusive uptake into 5-HT nerve terminals. The sensitivity of K+-stimulated release of [3H]5-HT to alpha 2-adrenoceptor occupancy was assessed in a superfusion system by means of the dose-dependent inhibition of [3H]5-HT release by clonidine. This is blocked by yohimbine (1 microM), which, when administered alone, enhances release, suggesting that endogenous catecholamines released from other synaptosomes act on these alpha 2-heteroreceptors. The effect of addition of citalopram (1 microM) to superfusates suggests that some reuptake of [3H]5-HT occurs during superfusion. Of the tritium released into superfusates during "background" and K+-stimulated release, 17 and 90%, respectively is [3H]5-HT. The attenuation of K+-stimulated release by clonidine is apparently diminished by the chronic clorgyline regimen but not by desipramine. However, clorgyline elevates catecholamine levels, and this might increase endogenous noradrenaline (NA) efflux, which by competition with clonidine could appear to alter alpha 2-adrenoceptor sensitivity. This possibility was investigated by depleting NA with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). These studies showed that the apparent effect of chronic clorgyline on alpha 2-adrenoceptor sensitivity to clonidine was due to competition with increased levels of endogenous NA.(ABSTRACT TRUNCATED AT 250 WORDS)

Presynaptic alpha 2- and postsynaptic beta-adrenoceptor sensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs

The effect of chronic (4 weeks) treatment of rats with the antidepressant drugs desipramine, maprotiline, chlorimipramine, zimelidine or iprindol on the sensitivity of presynaptic alpha 2- and postsynaptic beta-adrenoceptors in neocortical slices was investigated. Acute (1 day) treatment with the antidepressants did not affect the efflux of cyclic-AMP induced by isoprenaline (1 microM) from neocortical slices, while after chronic treatment the efflux of cyclic AMP was consistently reduced. Following acute administration the electrically-evoked release of [3H]noradrenaline (NA) from radiolabelled cortical slices remained unchanged. Upon chronic treatment with desipramine the release of [3H]NA was enhanced by about 45%. In contrast, after chronic treatment with maprotiline or chlorimipramine the electrically-evoked release of [3H]NA was not affected, whereas release was even slightly reduced after chronic administration of zimelidine or iprindol. In all cases, however, a similar inhibitory effect of exogenous NA (0.1 microM) on the release of [3H]NA was found. These data indicate that the desensitization of postsynaptic beta-adrenoceptors in rat brain after chronic treatment with antidepressant drugs is not paralleled by a reduction of presynaptic alpha 2-adrenoceptor sensitivity.

High-affinity uptake of choline in slices of rat cerebral cortex: effects of antidepressant and anticholinergic drugs.

The high-affinity uptake of choline by rat cerebral cortical slices was inhibited by high concentrations (10-100 microM) of the tricyclic antidepressant drugs imipramine, desipramine, and iprindole in vitro. However the nontricyclic antidepressant viloxazine did not affect choline uptake even at a concentration of 100 microM. None of the drugs had any effect on choline uptake by cortical slices when administered intraperitoneally (5, 10, 25 mg/kg) 30 min before sacrifice. Several anticholinergic drugs were tested for effects on in vitro uptake of choline. Hemicholinium-3 was a potent inhibitor of choline uptake but atropine, hexamethonium, and tubocurarine had no effect even at high concentrations (1000 microM).

7-(Aminoacyl) and 7-(aminoalkyl) derivatives of 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepines as potential antidepressant agents.

The synthesis of 7-(aminoacyl) and 7-(aminoalkyl) derivatives of 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepines is described. These compounds were evaluated for antidepressant activity by their ability to inhibit tetrabenazine-induced ptosis in mice. Many compounds were found to be active in this animal model, and structure-activity relationships are discussed. Two analogues in particular, one from the 7-(aminoacyl) series (13) and one from the 7-(aminoalkyl) series (26), were of comparable potency to the antidepressant drugs desipramine and amitriptyline.

Characterization and ontogenesis of [ 3H]-desipramine binding sites in developing fetal rat cerebral cells in culture

The tricyclic antidepressant drug desipramine (DMI) binds specifically to cultured cells from the fetal rat brain tissue in a saturable, displacable manner. The number of the binding sites is small during the first 48 hr in culture and increases markedly from day 4 and on, in a time-dependent course which parallels early synaptogenesis. DMI binding is effectively inhibited following chronic treatment of the cultures with 6-hydroxydopamine (6-OH-DA). In morphologically mature cultures, the IC 50 value of [ 3H]-DMI is 4 × 10 −6 M and the maximal number of binding sites is 160–200 pmoles/mg protein. The binding characteristics and the pharmacological profile of desipramine in developing cerebral cells are in excellent agreement with those found in adult rat brain.

Potentiation of responses of cortical neurones to 3,5-cyclic adenosine monophosphate by desipramine

Responses of cortical neurones to cyclic adenosine 3,5-monophosphate (cAMP) have been compared to responses of these neurones to noradrenaline (NA). All neurones depressed by NA were also depressed by cAMP. However, there was no such correlation between excitatory effects of the two substances. Depressant responses to cAMP and NA could be concurrently potentiated by the tricyclic antidepressant drug desipramine. It is suggested that the potentiation of responses to the two substances occurs by the same mechanism, possibly by post-synaptic inhibition of phosphodiesterase.

Net effect of acute administration of desipramine on the locus coeruleus — hippocampal system

The tricyclic antidepressant drug desipramine (DMI) produces multiple effects on noradrenergic nervous systems. This study attempted to determine the net outcome of these effects by evaluating the firing rate of noradrenergic postsynaptic neurons. Hippocampal pyramidal cells inhibited by stimulation of the nucleus locus coeruleus were used as noradrenergic postsynaptic neurons. An intraperitoneal injection of DMI (5 or 10 mg/kg) inhibited 14 of 23 cells studied and an intravenous injection (0.3 or 0.6 mg/kg) supressed 16 of 16 cells studied. The inhibition was pronounced and lasted 18 min (i.p.) or 8 min (i.v.). It was blocked by either locus coeruleus lesions or pretreatment with reserpine and α-methyl-p-tyrosine, which suggests that the inhibition was mediated by norepinephrine. These results indicate that the net effect of DMI on noradrenergic systems is facilitation.

Some clinical pharmacological studies with indoramin, with observations on its therapeutic usefulness

Summary In the treatment of fifteen patients with essential hypertension, in open trial indoramin caused a mean blood pressure fall from 180/115 mmHg to 159/98 mmHg. No reversal of antihypertensive effect was seen in four patients after additions of the tricyclic antidepressant drug desipramine. Blood pressure did not begin to rise in these four patients for at least 5 weeks after stopping indoramin. The implications of these findings are discussed.

The effect of some psychoactive drugs on central monoamine neurons

With the help of a histochemical and biochemical analysis of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in combination with the use of monoamine synthesis inhibitors (α-methyltyrosine methylester, α-propyldopacetamide), the effects of psychoactive drugs have been studied on central monoamine neurons of the rat. The results indicate that the antidepressive drugs desipramine, protriptyline and low doses of (+)-amphetamine do not influence the rate of NA and DA depletion after tyrosine-hydroxylase inhibition. One possible explanation for this lack of effect is that the stimulation of synthesis caused by the increased local loss of amine is counteracted by the negative feed-back on the presynaptic CA neuron, triggered by the increased amounts of transmitter reaching the adrenergic receptor sites. Large doses of (+)-amphetamine, on the other hand, increase the rate of amine depletion from the NA nerve terminals after tyrosine hydroxylase inhibition, whereas nialamide markedly reduces the rate of depletion. Chlordiazepoxide and phenmetrazine in the relatively high doses used do not seem to influence the activity of the central CA neurons. Desipramine and ethanol do not affect the activity of the 5-HT neurons, whereas pentobarbitone probably decreases their activity.