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PubMed1981

Brain distribution and kinetics of desipramine in the rat.

Pharmacokinetics and regional as well as subcellular brain distribution of desipramine (DMI) were investigated in male rats after single and repeated intraperitoneal administration. After a single dose DMI enters brain rapidly, accumulates with increasing the dose, and attains concentrations about 20 times those seen in plasma. After repeated administration peak plasma and brain levels were 2.7 and 3.7 times, respectively, higher than after a single dose. No significant regional differences were found in brain distribution or disappearance half-lives of the drug. After chronic treatment the drug was preferentially retained in the P2 fraction of brain homogenate; this may reflect the critical portion of drug bound to sites responsible for its pharmacological action.

Animals↗
PubMed1987

Effects of yohimbine and desipramine on cardiac noradrenaline release and ventricular arrhythmias during acute coronary artery occlusion and reperfusion in anesthetized dogs.

Effects of yohimbine (YHMB, an alpha 2-antagonist) and desipramine (DMI, a neuronal uptake inhibitor) were compared on cardiac noradrenaline (NA) release either upon left ansa subclavia nerve stimulation during acute occlusion of the left anterior descending coronary artery (LAD) or upon subsequent LAD reperfusion without stimulation in anesthetized dogs. In control dogs, before LAD occlusion, coronary sinus (CS) NA output increased from 5.4 +/- 1.0 to 26.8 +/- 4.0 ng/min (p less than 0.05) upon stimulation (2 Hz, 30 s). The response to stimulation remained unchanged 25 min after LAD occlusion. During reperfusion 60 min after occlusion, the output of CS-NA and lactate increased from 6.1 +/- 0.8 to 51.3 +/- 19.4 ng/min (p less than 0.05) and from 2.7 +/- 0.5 to 6.7 +/- 1.3 mg/min (p less than 0.05), respectively. In dogs treated with YHMB, the stimulation-induced increase in NA output was potentiated at least fourfold (p less than 0.05) either before or during LAD occlusion, but not during reperfusion. In dogs receiving DMI, stimulation-induced CS-NA output was enhanced to a similar extent (approximately twofold, p less than 0.05) either before or during occlusion, while reperfusion-induced NA output was markedly potentiated by approximately ninefold (p less than 0.05). Maximum dP/dt of left ventricular pressure remained unchanged upon reperfusion in all groups. The total arrhythmic ratio in the drug-treated groups did not significantly differ from the ratio in control dogs upon either stimulation or reperfusion. The data suggest that an abrupt increase in NA output upon reperfusion may result from a washout of NA locally accumulated in the ischemic and (or) peri-ischemic region during the preceding occlusion period, and that NA thus released does not have substantial hemodynamic effects. The results indicate that in the presence of YHMB or DMI, the potentiated increase in NA release in response to either nerve stimulation during LAD occlusion or to reperfusion without stimulation did not aggravate ventricular arrhythmia, most probably owing to the antiarrhythmic properties of these substances.

Anesthesia↗
PubMed1990

Effects of desipramine on norepinephrine clearance in congestive heart failure.

Elevated plasma norepinephrine (NE) in congestive heart failure (CHF) is caused by increased NE spillover and decreased NE clearance. To evaluate the effects of neuronal uptake blockade on NE clearance, we studied NE kinetics during steady-state infusions of [3H]NE, before and after oral desipramine (DMI, 50 mg) in 11 patients with CHF and 8 normal volunteers. Baseline plasma NE was greater in the CHF group (637 +/- 56 vs. 271 +/- 32 pg/ml; P less than 0.001), NE clearance was lower in CHF (1.31 +/- 0.21 vs. 1.94 +/- 0.17 l.min-1.m-2; P = 0.026), and NE spillover was greater in CHF (4.71 +/- 0.78 vs. 3.04 +/- 0.35 nmol.min-1.m-2, P = 0.054). After DMI, plasma NE rose significantly in CHF (778 +/- 67; P = 0.008), and NE clearance decreased further in CHF (0.97 +/- 0.16; P = 0.024), but neither changed in normal subjects. NE spillover did not change in either group. There appears to be an enhanced effect of DMI on NE clearance in CHF patients. Two general mechanisms may be responsible for this finding, an increased concentration of drug, possibly caused by a decreased volume of distribution, and an increased sensitivity of neuronal amine pumps to DMI. Both mechanisms may reflect a more general abnormality of clearance of drugs and hormones related to abnormalities of tissue perfusion in CHF.

Adult↗
PubMed1991

Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits.

Peripheral- and central nervous system (CNS)-mediated effects of desipramine (Des) on sympathetic nerves and the contribution of alpha 2-adrenoceptors to these effects were studied in conscious rabbits. Blood pressure, renal sympathetic nerve activity (SNA), and norepinephrine (NE) reuptake and spillover into plasma were measured before and after intracisternal (ic) or intravenous (i.v.) administration of Des. In other animals, NE spillover responses to i.v. Des were examined before and after alpha 2-adrenoceptor blockade with i.v. idazoxan. Treatment with i.v. Des blocked neuronal reuptake and decreased renal SNA but did not alter blood pressure or NE spillover. Decreased NE release by sympathetic nerves after i.v. Des was reflected by a decrease in the combined rate of NE reuptake and spillover. Treatment with ic Des (at 1.7% of the i.v. dose) decreased blood pressure and renal SNA and produced equivalent falls in NE reuptake and spillover, indicating little peripheral effect of centrally administered Des on the efficiency of neuronal reuptake. Thus Des had two distinct actions: the drug blocked neuronal reuptake by direct actions on nerve endings and reduced SNA by actions within the CNS. After ic Des, decreased SNA produced parallel falls in NE reuptake, spillover, and blood pressure. After i.v. Des, blockade of neurotransmitter reuptake increased NE concentrations at sympathoeffector junctions offsetting the fall in SNA, so that there was little change in NE spillover or blood pressure. However, after alpha 2-adrenoceptor blockade with i.v. idazoxan, NE spillover increased in response to i.v. Des. Thus the Des-induced decrease in NE release was partly mediated by an action of raised intrasynaptic NE concentrations on inhibitory alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1991

Effect of desipramine on norepinephrine metabolism in humans: interaction with aging.

To determine whether differences in neuronal reuptake contribute to age-related changes of sympathetic nervous system activity, we compared norepinephrine (NE) release and metabolism during [3H]NE infusion and decay in six young (age 19-26 yr) and seven older (age 61-73 yr) healthy nonobese subjects. Subjects were studied on a control day and on a separate day after desipramine (DMI; 125 mg orally), a neuronal reuptake blocker. Compartmental analysis of plasma NE specific activity was used to determine several NE kinetic parameters. Plasma NE levels and NE spillover rates were higher in the elderly. Although plasma NE was unaffected by DMI in both age groups, both the metabolic clearance rate of NE from plasma and the rate of NE spillover into plasma fell in young and older groups during DMI. Furthermore, DMI dramatically lowered the mass of NE in the extravascular compartment and the rate of NE entry into the extravascular compartment. Thus neuronal uptake blockade has major effects on NE release as well as NE metabolism in humans. However, age-related differences in NE kinetics cannot be explained by differences in neuronal uptake.

Adult↗
PubMed1982

Abnormal anterior pituitary responsiveness to hypothalamic hormones in primary affective disorders. Effect of desipramine therapy.

Abnormal anterior pituitary responsiveness to acute administration of thyrotropin-releasing hormone was investigated in 8 patients, 6 women and 2 men, with primary affective disorders in a depressive phase and in 2 women with schizoaffective disorders. Thyrotropin-releasing hormone, 500 micrograms i.v., induced a rise of plasma growth hormone levels in 1 patient suffering from primary affective disorders and in the 2 schizoaffective subjects, a rise of follicle-stimulating hormone in 1 schizoaffective patient, of luteinizing hormone in the 2 schizoaffective patients, an excessive prolactin rise in 5 patients with primary affective disorders and in 1 schizoaffective subject and a flat response of thyroid-stimulating hormone in 4 patients with primary affective disorders and in 2 schizoaffective patients. Desipramine was given at a dose of 50-100 mg/day for 3-5 weeks. The thyrotropin-releasing hormone stimulation test was repeated when the patients were improving or after 5 weeks of treatment without improvement. The hormonal impairments tended to disappear in those patients showing symptomatic improvement and were still present in those who did not improve.

Adult↗
PubMed1989

Cardiac beta-adrenergic sensitivity in depression: relation with endogenous subtype and desipramine response.

The authors studied the responsiveness of cardiac beta-receptors to isoproterenol, a noradrenergic agonist, in 29 depressed patients and 13 control subjects. They showed a significantly lower sensitivity in depressed patients as compared with the control subjects. Focussing on the group of depressed patients without antidepressant treatment in the month preceding the study (n = 15) in order to avoid a bias, the following significant results were obtained: cardiac beta-adrenergic receptor sensitivity was lower in patients suffering from endogenous depression than in those suffering from reactive depression (as classified by Newcastle Scale). There was a negative linear relation between cardiac beta-adrenergic sensitivity and the posttreatment clinical state (as expressed by the MADRS score) for the 9 patients who ended a 3-week desipramine treatment period.

Adjustment Disorders↗
PubMedDate not supplied

Imipramine and desipramine decrease the GABA-stimulated chloride uptake, and antigabaergic agents enhance their action in the forced swimming test in rats.

The present study reports that long-term (18 days) administration of imipramine (IMI, 20 mg/kg) or desipramine (DMI, 15 mg/kg) produced a significant decrease in the GABA-stimulated 36Cl- uptake into membrane vesicles from the cerebral cortex of rats (experiment 1). Experiments 2A, B show that anti-immobility effects of DMI and IMI (subacute treatment) in the forced swimming test are enhanced when a single subconvulsant injection of picrotoxin or pentylenetetrazol is administered to the animals concurrently to the last antidepressant injection. These results are discussed in relation with a current GABAergic hypothesis of depression and antidepressant drug action.

Animals↗
PubMed1984

Effects of desipramine on clinical liver function tests.

Results of liver function tests in 46 depressed patients changed little during treatment with desipramine and were uncorrelated with drug plasma levels. The findings suggest that tricyclic-associated hepatitis, rather than being dose dependent, is an uncommon, idiosyncratic phenomenon.

Adult↗
PubMed1986

Pharmacokinetics of desipramine in Caucasian and Asian volunteers.

The plasma levels of 20 healthy Asian subjects who received a single dose of desipramine were compared with those of 20 healthy Caucasian subjects who received such a dose. The groups differed significantly only in that Asian subjects had an earlier time of peak serum concentration.

Adult↗
PubMed1994

Desipramine for the treatment of "pure" dysthymia versus "double" depression.

The authors report results of an 8-week, open trial of desipramine in 42 patients with DSM-III-R dysthymia with a concurrent diagnosis of major depression ("double" depression) and 33 patients with dysthymia who had no other depressive diagnosis ("pure" dysthymia). Either complete or partial remission was achieved by 70% of the patients with "pure" dysthymia. This compared favorably with but was not significantly different from results in the "double" depression group.

Adult↗
PubMed1985

Desipramine-induced delirium at "subtherapeutic" concentrations: a case report.

An elderly patient treated with low dose Desipramine developed a delirium while her plasma level was in the "subtherapeutic" range. Delirium, which may be induced by tricyclic drug therapy in the elderly, can be caused by tricyclics with low anticholinergic potency. Therapeutic ranges for antidepressants that have been derived from general adult population studies may not be appropriate for the elderly. Further studies of specifically elderly patients are now required to establish safer and more appropriate guidelines for drug therapy.

Age Factors↗
PubMed1987

Desipramine: a possible treatment for depersonalization disorder.

Primary depersonalization disorder is believed to be resistant to treatment. However, we report the successful treatment of a case with desipramine and suggest that, because there is a link between depersonalization and anxiety disorders, tricyclic antidepressants may prove effective for depersonalization.

Adolescent↗
PubMed1990

Lithium carbonate augmentation of desipramine in refractory depression.

An open clinical study with 20 consecutive outpatients suffering from major depression with melancholia (DSM-III) was carried out. All patients were resistant to desipramine after at least six weeks of treatment. A significant improvement was found in 13 of the 20 patients when lithium carbonate was added. Among the responder patients, five improved in the first week of lithium augmentation, while eight others improved after one week of lithium. The mechanism of action of the lithium augmentation effect in tricyclic-resistant depressed patients is discussed in view of our findings. We suggest that the unified 5-HT/NE hypothesis used in affective disorder could be applied in drug refractory depression.

Depressive Disorder↗