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PubMedDate not supplied

A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer.

BACKGROUND: This study was conducted to determine the efficacy and tolerability of fluoxetine and desipramine in treating depressive symptoms in women with cancer. METHOD: In this prospective, 6-week, double-blind, placebo-controlled trial, we compared fluoxetine with desipramine in treating depressive symptoms in 40 women diagnosed with cancer. Scales used to measure efficacy and tolerability were the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale (HAM-A), the Clinical and Patient's Global Impression (CGI and PGI) scales, the Functional Living Index for Cancer (FLIC), the Memorial Pain Assessment Card (MPAC), and the SF-36 Health Survey. RESULTS: Fluoxetine and desipramine treatments improved depression and anxiety symptoms. There was a trend towards significance in improvement of FLIC scores (as evidenced by greater numerical improvements with fluoxetine treatment). Fluoxetine treatment alone was associated with statistically significant improvements in MPAC Mood scale scores. Both treatments showed statistically significant improvements in the quality of life SF-36 scores in Role Emotional, Social Functioning, Mental Health, and Vitality. CONCLUSIONS: Both fluoxetine and desipramine were effective and well-tolerated in improving depressive symptoms and quality of life in women with advanced cancer. Fluoxetine may offer greater benefit to these patients, as evidenced by greater improvements in fluoxetine-treated patients on several quality of life measures. Our results, while meaningful, should be confirmed in a larger patients sample. However, experience from studies of antidepressant use in patients with advanced cancer has shown that intercurrent disease and treatment variables make it difficult to conduct large studies.

Antidepressive Agents, Second-Generation↗

PubMed1983

Effect of desipramine and cocaine on plasma norepinephrine and pressor responses to adrenergic stimulation in pithed rats.

Sympathetic neuronally released norepinephrine appears to act at intrajunctional alpha 1-adrenoceptors, whereas administered norepinephrine acts mostly at extrajunctional alpha 2-adrenoceptors. We examined the effects of inhibition of neuronal uptake of norepinephrine by desipramine (0.3 mg/kg iv) and cocaine (5 mg/kg iv) on the pressor effects and on plasma norepinephrine levels in pithed rats after the administration of norepinephrine (0.1, 0.3, and 1.0 micrograms/kg iv) or during stimulation of sympathetic outflow (0.1, 0.3, and 1.0 Hz at 50 V for 1 minute). Desipramine and cocaine potentiated the cardiovascular effects of administered norepinephrine to a greater extent than they potentiated the effects of sympathetic stimulation. Plasma levels of norepinephrine during sympathetic stimulation or after iv administration of norepinephrine were increased significantly after either desipramine or cocaine. The cardiovascular effects of sympathetic stimulation, but not of exogenous norepinephrine, were reduced in adrenomedullectomized rats compared to intact rats. In adrenomedullectomized rats, desipramine potentiates the pressor responses and enhances the increase in plasma norepinephrine levels during sympathetic stimulation to the same extent as in intact pithed rats. The preferential potentiation of administered norepinephrine by uptake inhibition is most likely due to enhancement of accessibility of circulating norepinephrine to otherwise inaccessible intrajunctional alpha 1-adrenoceptors. The higher concentrations of norepinephrine in the region of the nerve-ending limit release of the neurotransmitter by feedback inhibition via presynaptic alpha 2-adrenoceptors, thereby masking potentiation by uptake inhibition of the postsynaptic responses to sympathetic stimulation.

Animals↗

PubMed1989

Antiarrhythmic efficacy of desipramine.

The effect of desipramine on chronic ventricular ectopic depolarizations (VEDs) was studied in 10 patients with at least 30 VEDs per hour. A single-blind, placebo-controlled, dose-ranging protocol was followed. Efficacy was defined as a decrease in VED frequency of at least 75%, base on three 24 hour ambulatory ECGs obtained on each dose. Among seven patients with analyzable data, one responded to 75 mg daily, and three others responded to 150 mg daily. Six of the seven patients demonstrated decreases in VED frequency with increases in desipramine serum concentration. Among five patients with episodes of nonsustained ventricular tachycardia, desipramine completely abolished the episodes in two, and reduced the frequency of episodes by at least 90% in two others. Adverse reactions were common, and necessitated drug discontinuation or dose reduction in five patients. Desipramine has an antiarrhythmic effect in patients with chronic ventricular ectopy, but its clinical utility is limited by adverse effects.

Adult↗

PubMed1995

Cloning, expression, and purification of an anti-desipramine single chain antibody in NS/O myeloma cells.

Drug-specific monoclonal antibodies and their antigen-binding Fab fragments reverse acute desipramine toxicity in a rat experimental model by inducing a redistribution of drug from cardiac tissue into serum and extracellular fluid. In order to investigate the use of smaller recombinant antibody fragments such as single chain Fv (sFv) as an antidote, an efficient murine NS/O myeloma expression system was developed. The variable light (VL) and variable heavy (VH) domains of a murine anti-desipramine monoclonal antibody were cloned and sequenced. A 270 amino acid VH-(Gly4Ser)3-VL sFv was prepared by overlapping polymerase chain reaction (PCR) amplification of VH with heavy chain leader peptide, VL, and the linker. This construct was subcloned into a mammalian expression vector which utilizes the SR alpha promoter, a hybrid promoter consisting of the SV40 early promoter with portions of the human T-cell leukemia virus type I long terminal repeat and also containing the Escherichia cloi xanthine-guanine phosphoribosyltransferase gene for selection. NS/O myeloma cells were transfected by electroporation. Stable recombinant NS/O clones were screened for expression of sFv using reverse transcriptase-PCR to detect mRNA and an enzyme-linked immunosorbent assay (ELISA) to detect sFv. Secreted sFv from clones capable of growth to a cell density of 2-4 x 10(6) viable cells/mL was purified in a single step using a desipramine affinity column resulting in 12-39 mg/L of purified sFv. Affinity-purified sFv had comparable desipramine binding activity to Fab when evaluated by competitive ELISA.

Amino Acid Sequence↗

PubMed1984

Cimetidine-induced alterations in desipramine plasma concentrations.

Concurrent administration of cimetidine for 4 days to eight patients taking maintenance doses of desipramine led to significant elevations of desipramine (P less than 0.001) and its hydroxylated metabolite 2-hydroxydesipramine (P less than 0.001). The mean increase in desipramine plasma levels was 51% and that for 2-hydroxydesipramine was 46%. The present results suggest that tricyclic antidepressant plasma level monitoring might be indicated for certain patients taking concurrent cimetidine and desipramine.

Adult↗

PubMed1989

Quinidine inhibits the 2-hydroxylation of imipramine and desipramine but not the demethylation of imipramine.

On separate occasions 6 extensive metabolizers of sparteine took a single oral dose of 100 mg imipramine and desipramine before and during the intake of quinidine sulphate 200 mg/day. During quinidine the total oral clearance of imipramine on average was reduced by 35%, and that of desipramine by 85%. The clearance of imipramine via demethylation was not significantly reduced during quinidine administration, whereas its clearance by other pathways, largely 2-hydroxylation, was reduced by more than 50%. 2-OH-Imipramine and 2-OH-desipramine were detected in plasma before (maximum concentrations 30-100 nmol.l-1) but not during quinidine. It appears that quinidine is a potent inhibitor of the sparteine/debrisoquine oxygenase, P450dbl, which is responsible for the 2-hydroxylation of imipramine and desipramine, but not of the P450 isozyme responsible for the demethylation of imipramine.

Adult↗

PubMed1987

Effects of desipramine on irritable bowel syndrome compared with atropine and placebo.

Antidepressant treatment trials of irritable bowel syndrome (IBS) have suggested beneficial effects. Twenty-eight patients with the disorder (9 constipation-predominant, 19 diarrhea-predominant) completed a double-blind crossover study using desipramine, atropine, and placebo in random sequence. A four-week observation period preceded three six-week test periods. Bowel habits, abdominal distress, and affect were reported daily and in biweekly evaluations. Psychological assessments and rectosigmoid contractile studies were done in each period. Stool frequency, diarrhea, abdominal pain, depression, and slow contractions decreased significantly more in diarrhea-predominant patients during desipramine compared with placebo and atropine treatments. Diarrhea-prone patients' depression scores fell more in all periods than constipation-prone patients. Fifteen patients (13 diarrhea-predominant) improved globally during desipramine, five during placebo and six during atropine treatments. Desipramine may be helpful in treating IBS, perhaps through antidepressant and antimuscarinic effects.

Adult↗

PubMed1993

Beta-receptor responsiveness after desipramine treatment.

To examine whether a tricyclic antidepressant affects the functional response to a beta-receptor agonist in man, the response of heart rate, blood pressure, and plasma cAMP to isoproterenol was measured in 14 normal controls taking 75 mg desipramine daily. Desipramine significantly increased the bolus dose of isoproterenol needed to increase heart rate by 25 bpm at 14-30 days but not at 3-8 days. During infusions of isoproterenol, the increase in systolic blood pressure was blunted at both 3-8 days and 14-30 days, while the decrease in diastolic blood pressure was unaffected. Blood pressure findings were not affected by preadministration of bethanechol. In ten controls, isoproterenol infusions increased plasma cAMP, but this was unaffected by desipramine treatment. These findings suggest a decrease in the functional response of beta 1, but not beta 2, receptors after treatment with desipramine.

Adult↗

PubMed1996

Effects of desipramine and fluvoxamine on timing behavior investigated with the fixed-interval peak procedure and the interval bisection task.

Acute treatment with antidepressant drugs is known to increase the mean interresponse time (IRT) in the IRT > 72-s schedule of reinforcement. In order to examine the possibility that this effect may reflect an action of the antidepressants on timing processes, we tested the effects of two antidepressants, desipramine and fluvoxamine, on behaviour maintained under two other timing schedules in rats. In the fixed-interval peak procedure (fixed-interval 30-s), acute treatment with desipramine (8 mg kg-1) reduced response rate, whereas acute treatment with fluvoxamine (8 mg kg-1) increased it. Neither drug significantly altered the time to attainment of peak response rate or the Weber fraction. In the interval bisection task (standard durations 2 s and 8 s), the bisection point was not significantly altered by acute treatment with either drug. Chronic treatment with desipramine (8 mg kg-1 b.d.) had no effect on any of the indices of timing under either schedule. Chronic treatment with fluvoxamine (8 mg kg-1 b.d.) reduced the time to attainment of peak response rate but had no effect on the Weber fraction under the fixed-interval peak procedure, and did not alter the bisection point or Weber fraction under the interval bisection procedure. The failure of desipramine and fluvoxamine to increase the time to peak response rate or the bisection point at doses that significantly altered operant response rate suggests that the effect of these drugs on IRT schedule performance is unlikely to reflect an interaction with timing processes.

Adrenergic Uptake Inhibitors↗

PubMed2004

Comparative effects of duloxetine and desipramine on sleep EEG in healthy subjects.

RATIONALE: Antidepressants are known to modify human sleep patterns. OBJECTIVES: Duloxetine is a new antidepressant with a mechanism of action involving reuptake inhibition of both serotonin (5-HT) and norepinephrine (NE). In this study, the effects of two dosing regimens of duloxetine on sleep electroencephalography (EEG) were investigated at steady-state plasma concentrations in young, healthy, male subjects. METHODS: Placebo (n=12), desipramine (50 mg BID; n=12) and two regimens of duloxetine (80 mg QD, n=6; or 60 mg BID, n=6) were compared in a randomized, double-blind, three-period crossover study, each treatment being administered from day 1 to day 7. Sleep polygraphic recordings took place at baseline (day -1) and day 6 of each period. The Leeds sleep evaluation questionnaire (LSEQ) was also administered on the morning of day 7. RESULTS: Both regimens of duloxetine produced a significant increase in the onset latency of REM sleep as well as a significant mean decrease in total REM sleep duration. Desipramine exhibited comparable effects. When compared to placebo, sleep continuity was significantly reduced with desipramine and duloxetine 60 mg BID whereas a significant improvement was observed with duloxetine 80 mg QD. On the LSEQ, duloxetine 80 mg QD produced a significant improvement in the "getting to sleep" subscale compared to placebo, whereas desipramine demonstrated a significant reduction (worsening) in the "quality of sleep" score versus placebo. CONCLUSIONS: The two dose regimens of duloxetine (80 mg QD and 60 mg BID) produced a REM sleep pattern comparable to that of most antidepressant medications. Duloxetine 80 mg QD appeared to exhibit less impact upon sleep quality than duloxetine 60 mg BID in healthy subjects.

Adolescent↗

PubMed1999

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

RATIONALE: The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. OBJECTIVES: The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. METHODS: Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. RESULTS: Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. CONCLUSIONS: Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

Animals↗

PubMed2001

Duplication of CYP2D6 predicts high clearance of desipramine but high clearance does not predict duplication of CYP2D6.

OBJECTIVE: Duplication of CYP2D6 causes very rapid metabolism of CYP2D6 substrates such as desipramine. However, we have previously shown that in the Danish population, only about 15% of very rapid metabolisers, defined as subjects with a metabolic ratio of sparteine of 0.15 or less, carried a duplicated allele. The question is whether gene duplication is a relatively rare cause (perhaps predictor) of very rapid metabolism or whether a low metabolic ratio is a poor predictor of this. METHODS: After measuring metabolic ratios anew, we selected six volunteers with duplication of CYP2D6 and metabolic ratios ranging from 0.07 to 0.17 and six volunteers without duplication with metabolic ratios ranging from 0.08 to 0.21. Each subject took 100 mg of desipramine. Blood and urine were collected for 48 h. RESULTS: The median total oral clearance of desipramine was 372 l/h and 196 l/h [median difference 108 l/h (95.9% c.i., -304-598 l/h)] and the median partial clearance of desipramine by 2-hydroxylation was 155 l/h and 87 l/h [median difference 47 l/h (95.9% c.i., -124-141 l/h)] for the group with duplication and the group without duplication, respectively. CONCLUSION: The predictive value of duplication of CYP2D6 is poor; there must be other causes (or predictors) of very rapid metabolism and with much higher frequency than duplication of CYP2D6.

Administration, Oral↗

PubMed1994

Comparison of cognitive-behavior therapy and desipramine in the treatment of bulimia nervosa.

A comparison of cognitive-behavior therapy alone, desipramine alone, and cognitive-behavior therapy combined with desipramine was made in the treatment of bulimia nervosa. The study was terminated early with an N of only 7 subjects per condition because of a high drop-out rate and lack of positive response in the desipramine alone group compared to the other two groups. By this time it was also apparent that at posttreatment and at 6 months follow-up no benefit was being realized from combining cognitive-behavior therapy with desipramine.

Adolescent↗

PubMed1988

Effects of lithium and desipramine administration on agonist-stimulated inositol phosphate accumulation in rat cerebral cortex.

The effects of acute lithium and chronic desipramine administration on the inositol phosphate responses of rat cerebral cortical slices to noradrenaline, carbachol and 5-hydroxytryptamine, were determined. Acute injection of lithium (4 meq/kg s.c. 24 hr before sacrifice) significantly increased the inositol-1-phosphate response to noradrenaline, while chronic administration of desipramine (10 mg/kg i.p. for 3 weeks) produced a smaller increase in this parameter. Chronic desipramine also decreased the serotonin responses in terms of all three inositol phosphates measured. No potentiative or additive interactions between the lithium and desipramine effects were observed.

Animals↗

PubMed1990

Kinetic properties of the metabolism of imipramine and desipramine in isolated rat hepatocytes.

The metabolism of imipramine and desipramine was examined by using isolated rat hepatocytes. The enzyme systems having high-affinity-and-low-capacity and low-affinity-and-high-capacity kinetic properties were found to catalyze aromatic 2-hydroxylations of imipramine and desipramine, and aliphatic N-demethylation of imipramine, respectively. The Km and Vmax values for N-demethylation of imipramine (which formed desipramine) were about 5-10 and 5 times larger than those of both 2-hydroxylations respectively. A competitive inhibition between the 2-hydroxylations of imipramine and desipramine ("parallel pathway interaction") (Chiba M, Fujita S and Suzuki T, J Pharm Sci 77: 944-947, 1988), observed using liver microsomes, was found also in isolated hepatocytes. It was concluded that the characteristics of imipramine metabolism observed in liver microsomes were well reproduced in isolated rat hepatocytes.

Animals↗

PubMed1989

Differences between sodium-dependent and desipramine-defined [3H]imipramine binding in intact human platelets.

Measurements of sodium-dependent [3H]imipramine binding to intact human platelets from 20 human volunteers were made and compared to desipramine-defined binding, a method commonly employed in population studies of platelet [3H]imipramine sites. The density (Bmax) of sodium-dependent [3H]imipramine sides in platelets was significantly lower (449 +/- 36 sites/platelet) and the affinity (Kd) significantly higher (1.15 +/- 0.12 nM) than those obtained when excess desipramine was used to define specific binding (Bmax 654 +/- 33 sites/platelet, p less than 0.001; Kd 1.52 +/- 0.11 nM, p less than 0.001). There was no significant correlation between the density (Bmax) of sodium-dependent and desipramine-defined binding in individual subjects, suggesting that a different proportion of sites are labeled under the two assay conditions. No age-dependent variation was found in either Kd or Bmax values of sodium-dependent or desipramine-defined [3H]imipramine binding. The results suggest determination of sodium-dependent [3H]imipramine binding to intact platelets may be a useful measure for the estimation of [3H]imipramine recognition sites relevant to the serotonin uptake in studies of patients with affective disorders.

Adult↗

PubMed1991

Chronic desipramine treatment reduces regional neuropeptide Y binding to Y2-type receptors in rat brain.

Chronic treatment of rats with desipramine and imipramine (5 mg/kg/twice daily/i.p.) for 14 days caused a significant reduction in the binding of [3H]propionyl NPY to membranes prepared from frontal cortex, nucleus accumbens, hypothalamus and hippocampus. There was no change in binding of [3H]propionyl NPY in the parieto-occipital cortex, striatum or amygdala. Scatchard analysis of binding data from frontal cortical and hippocampal membranes showed that [3H]propionyl NPY bound to a single site with a Kd of approximately 0.3 nM. The loss of [3H]propionyl NPY binding in hippocampal and frontal cortical membranes revealed that chronic tricyclic antidepressant treatment produced a reduction in the number of binding sites with no change in the affinity for the ligand. Chronic desipramine treatment did not alter the ability of NPY (0.01-25 microM) to stimulate inositol phosphate accumulation in rat frontal cortical slices as compared to saline-treated animals. The lack of change of NPY-induced inositol phosphate accumulation following chronic desipramine treatment showed that there was no change to Y1 NPY-type receptors which are linked to the hydrolysis of inositol phospholipids. However, the ability of NPY (0.05-0.5 microM) to inhibit forskolin (1 microM) stimulated adenylate cyclase via Y2 NPY-type receptors in rat frontal cortical slices was significantly reduced following chronic desipramine treatment. This finding suggests that the reduction of [3H]proprionyl NPY binding in selective brain regions may be the result of an antidepressant-induced loss of Y2-type NPY receptors which are negatively linked to adenylate cyclase.

Animals↗

PubMed1984

Effect of steroids on the inhibition of platelet 5HT uptake by desipramine and other antidepressants.

The inhibitory effect of desipramine on platelet 5HT uptake was tested ex vivo and in vitro in control, adrenalectomised and triamcinolone-treated rats. In both situations, the inhibitory effect of desipramine was augmented in adrenalectomised rats and decreased in triamcinolone-treated rats. These changes in desipramine sensitivity were accompanied by changes in the uptake kinetic components, Km and Vmax. In in vitro studies, the IC50 of clomipramine, fluvoxamine, zimelidine, imipramine and nomifensine was decreased in adrenalectomised rat platelets and increased in corticosterone-, dexamethasone- or triamcinolone-treated rat platelets. Deoxycorticosterone had no effect. Testosterone only affected the IC50 of desipramine and nomifensine.

Adrenalectomy↗