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PubMed2001

Lesion of the bulbospinal noradrenergic pathways blocks desipramine-induced inhibition of the C-fiber evoked nociceptive reflex in rats.

Desipramine-induced inhibition of spinal cord nociceptive transmission was studied in rats with or without lesion of the bulbospinal noradrenergic system by recording the C-fiber evoked nociceptive reflex from a hind limb. Bulbospinal noradrenergic projections were lesioned by injecting intrathecally 20 microg of 6-hydroxydopamine 2 weeks before the electrophysiological experiments. Results show that desipramine (5, 10 and 20 mg/kg intraperitoneally) produced dose-dependent inhibition of the C reflex response duration in rats having intact noradrenergic bulbospinal systems. The inhibitory effect of desipramine was reduced or even abolished in rats pre-treated with 6-hydroxydopamine. In addition, [3H]-noradrenaline uptake was significantly lower in spinal cord slices arising from 6-hydroxydopamine lesioned animals, as compared to that from intact rats. These observations support the notion that the antinociceptive activity of antidepressants with noradrenergic selectivity depends on a normal rate of endogenous noradrenaline released by bulbospinal neurons.

Adrenergic Agents↗

PubMed1997

The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization.

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10-100 mg/kg, s.c.) significantly (P < 0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1-100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P < 0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3-30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different.

Animals↗

PubMed2002

The SSRIs drug Fluoxetine, but not the noradrenergic tricyclic drug Desipramine, improves memory performance during acute major depression.

Accumulating evidence suggests that noradrenergic and serotonergic drugs are equally effective in ameliorating the depressive symptoms of major depression. Major depression is associated also with memory impairments, but the comparative effects of the antidepressant drugs on memory are not clear. We previously found that serotonergic neurotransmission is of particular importance for some aspects of episodic memory. We set out to test whether treatment with the selective serotonergic drug Fluoxetine (Prozac) would be advantageous in this respect over treatment with the selective noradrenergic tricyclic antidepressant drug Desipramine (Deprexan). Seventeen patients with major depressive episode, randomly assigned for treatment with either Fluoxetine (n = 8) or Desipramine (n = 9), were assessed for their clinical situation and for memory performance at the beginning of treatment, after 3 weeks, and after 6 weeks of pharmacological treatment. We found that although clinically both drugs were equally effective, the improvement of memory performance in the Fluoxetine-treated patients was significantly greater compared with that of the Desipramine-treated patients. The results support the role of serotonin in memory. More studies in larger samples of patients are required, but it may be that in cases where memory impairment is a major symptom, it would be beneficial to consider serotonergic antidepressant drugs for treatment. Furthermore, in cases where, for various reasons, the treatment of choice is noradrenergic, it may be worthwhile to consider a supplementary serotonergic drug to improve memory deficits.

Acute Disease↗

PubMed1999

Desipramine treatment decreases 3H-nisoxetine binding and norepinephrine transporter mRNA in SK-N-SHSY5Y cells.

The antidepressant desipramine has been shown to decrease synaptic membrane concentrations of the norepinephrine re-uptake transporter (NET) in vivo and in vitro, on both an acute and a chronic basis. The possible contribution of decreased NET synthesis to the chronic downregulation of the NETs has not been definitively established. In this study, we treated SK-N-SHSY5Y cells with 100 nM desipramine for 24 or 72 h, and measured 3H-nisoxetine binding (as an estimate of NETs) and NET mRNA by quantitative reverse transcription polymerase chain reaction. Similar to what has been reported previously, membrane 3H-nisoxetine binding was significantly decreased at both 24 and 72 h (approximately 50% at both time points). However, a significant decrease (64 +/- 8% of paired control) of NET mRNA was observed only at the 72-h time point. We conclude that decreased NET synthesis may contribute to the chronic, but not acute, effect of desipramine to downregulate the NET.

Adrenergic Uptake Inhibitors↗

PubMed1983

Thin-layer chromatographic determination of imipramine and desipramine in human plasma and urine at single-dose levels.

Thin-layer chromatographic methods were up-dated for pharmacokinetic studies of imipramine in plasma and urine. The free parent compound and its free desmethyl metabolite desipramine are determined in plasma. Conjugates of both compounds in urine are cleaved on treatment with glucuronidase/arylsulfatase. Following chromatography, intense yellow derivatives are obtained overnight on standing or by exposure to nitrous gases. Detection is performed in the visible range at 405 nm (plasma) or 460 nm (urine). The methods are selective, accurate and sensitive, with detection limits for plasma of 2 ng/ml imipramine--HCl and 2 ng/ml desipramine--HCl, and 0.06 micrograms/ml total imipramine--HCl and 0.126 micrograms/ml total desipramine--HCl for urine. Pharmacokinetic data from plasma and urine results following single oral doses of 50 mg imipramine--HCl to eight volunteers were computed using one-compartment open models.

Adult↗

PubMed1997

Sensitive microanalysis of imipramine and desipramine in single rat thyroids by gas chromatography-mass spectrometry.

A new sensitive method for the quantitative determination of imipramine and desipramine in single rat thyroids using gas chromatography-mass spectrometry with selected ion monitoring, after enzymatic hydrolysis and liquid-liquid extraction has been developed. The technique was deemed suitable for microanalysis of single rat thyroids and for other solid tissues, using smaller sample sizes than usually required for traditional determination methods. The quantification was linear from 10 to 200 nmol/l (i.e., from 0.25 to 5 microg/g) for imipramine and from 100 nmol/l to 2000 nmol/l (i.e., from 2.4 to 47 microg/g) for desipramine, and the limits of detection (less than 25 ng/g tissue for both compounds) were better than those previously reported. Recoveries, repeatability and reproducibility of this technique were satisfactory. It has been successfully applied in a preliminary study of the concentration-time profiles of imipramine and desipramine in the thyroid of rats treated with either of these drugs.

Animals↗

PubMed2001

Cerebral blood flow in obsessive-compulsive patients with major depression: effect of treatment with sertraline or desipramine on treatment responders and non-responders.

We examined the effects of sertraline and of desipramine on patients with OCD and comorbid major depressive episodes at study entry. Sixteen patients, 9 receiving sertraline and 7 desipramine, received HMPAO SPECT scans while free of medication and after 12 weeks of treatment. Patients on sertraline showed significantly reduced regional cerebral blood flow (rCBF) in the right prefrontal and temporal regions. Patients on desipramine showed more diffuse rCBF reductions in frontal and temporal regions, more so in the left side. In a second analysis, patients who had a symptom reduction on the Yale-Brown Obsessive Compulsive Scale (YBOCS), irrespective of the type of medication, were retrospectively classified as 'responders' to treatment. Eleven patients were 'responders' and 5 'non-responders'. Before being medicated, responders differed from non-responders through higher rCBF in prefrontal regions, mostly on the left, and higher rCBF in the cingulate and basal ganglia bilaterally. After 12 weeks of treatment, responders showed a diffuse reduction of rCBF in prefrontal regions while non-responders showed only a few scattered low-frequency responses. Thus, higher prefrontal and subcortical activity was associated with better response to drug treatment. In addition, clinical change, but not the administration of medication as such, was associated with a decrease of prefrontal rCBF.

Adult↗

PubMed2004

Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex.

Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The current study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration of methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, whereas methamphetamine interacts minimally with norepinephrine transporters.

Amphetamine↗

PubMed1980

Anticholinergic effects and plasma desipramine levels.

Anticholinergic effects of the tricyclic antidepressant desipramine were studied in 12 outpatients. Objective measurements of salivation and pulse rate and subjective ratings of mouth dryness and palpitations were made before and during treatment with desipramine at a final daily dosage of 150 mg. There were significant changes after 3 wk of treatment in all parameters except ratings of palpitation. Subjects with moderate or high plasma desipramine levels had more suppression of salivation than those with low levels. Changes in salivation and pulse did not correlate, nor did they correlate with subjective reports.

Adult↗

PubMed1987

Differences in the inhibitory effect of cimetidine on desipramine metabolism between rapid and slow debrisoquin hydroxylators.

The disposition of a 25 mg single oral dose of desipramine was investigated in five rapid and four slow hydroxylators of debrisoquin before and during oral administration of 1200 mg cimetidine daily. AUC and elimination half-life of desipramine increased during cimetidine administration in rapid but not in slow hydroxylators. This was the result of a decrease in overall clearance. The urinary recovery of 2-hydroxydesipramine was significantly decreased in rapid hydroxylators during cimetidine administration. We conclude that cimetidine inhibits the metabolism of desipramine in rapid but not in slow hydroxylators.

Adult↗

PubMed1987

Nonlinear desipramine kinetics: prevalence and importance.

Tricyclic antidepressant plasma levels have been used to guide dose adjustment in nonresponding patients, and recently 24-hour drug levels have been advocated for predicting therapeutic doses. Both methods of dose adjustment assume linear drug kinetics. Recent reports have suggested that desipramine kinetics are nonlinear, but the samples described were small, six subjects or fewer. In the current study, plasma desipramine concentrations were examined in 42 inpatients who were depressed who had achieved steady-state conditions with a low initial dose and subsequently with a higher dose. Desipramine concentrations increased significantly more than that predicted by the dose increase; however, only one third of the sample had substantial nonlinear changes (an increase in the concentration 50% greater than expected). In the remainder of the sample, disproportionate increases in plasma concentrations were not likely to be of clinical consequence.

Adolescent↗

PubMed1993

Central analgesic effects of desipramine, fluvoxamine, and moclobemide after single oral dosing: a study in healthy volunteers.

The antinociceptive effect of three antidepressants with different postulated modes of action, 75 mg desipramine, 225 mg fluvoxamine, and 450 mg moclobemide, was evaluated after single oral dosing in a randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. Experimental pain thresholds (polysynaptic R-III reflex and subjective pain rating) were monitored over 23 hours. Compared with placebo, all drugs induced significant subjective pain threshold increases (maximal increase: desipramine, +20%; fluvoxamine, +17%; moclobemide, +13%). However, only desipramine (maximal increase, +25%) and moclobemide (maximal increase, +14%) displayed a significative effect on R-III threshold. Antidepressants thus exert an antinociceptive effect after a single oral dose. The level of their action apparently relies on the postulated mode of action.

Administration, Oral↗

PubMedDate not supplied

Antidepressant treatment of chronic tension-type headache: a comparison between fluoxetine and desipramine.

Amitriptyline, which is a noradrenaline reuptake and 5-HT reuptake inhibitor, has an established role in the management of chronic tension-type headaches. In a single-blind study, patients with chronic tension-type headache were randomized to either fluoxetine 20 mg (a selective 5-HT reuptake inhibitor) or desipramine 75 mg (a selective noradrenaline reuptake inhibitor) and followed for 12 weeks to compare the effectiveness of the two drugs in improving headache, and to assess whether pain control is related to changes in depression. Patients were evaluated at weekly intervals on an analog pain-rating scale and at 4-weekly intervals on the Montgomery and Asberg Depression Rating Scale (MADRS), the MOS general health status questionnaire (SF36), the Hospital Anxiety and Depression Scale (HADS), and a side effects checklist. Eighteen patients were randomized to take fluoxetine and 19 to take desipramine. Of the 25 patients who completed the trial, 12 were on fluoxetine and 13 were on desipramine. There was no significant difference between the two groups at baseline nor in change of pain; reduction in use of analgesic medication; nor change in the HADS, MADRS, or SF36 scores at 12 weeks, but 72% of patients who completed the study improved, and this improvement almost exactly mirrored the improvement on the MADRS. The results from this trial are compatible with the notion that the beneficial effect of antidepressants in chronic tension-type headache is indirect, mediated by an effect on depression, and not more,dependent on serotonin reuptake inhibition than noradrenaline reuptake inhibition.

Adolescent↗

PubMed1990

Desipramine induces cardiac beta-adrenergic sensitivity decrease in major depressed patients without relationship to therapeutic response.

Nineteen major depressed inpatients were treated over three weeks with desipramine. Cardiac beta-adrenergic receptor sensitivity was evaluated by an isoproterenol test before and after the three-week treatment. Desipramine induced a beta-adrenergic sensitivity decrease in most of the patients: I 20 (isoproterenol dose necessary to increase by 20 beats/min. the basal heart rate) before treatment: 89 +/- 37 ng/kg (mean +/- SD); after treatment: 170 +/- 135 ng/kg; p(t) less than 0.03. Despite a linear relationship between pretreatment beta-adrenergic sensitivity and post-treatment clinical state, there was no relation between post-treatment cardiac beta-adrenergic sensitivity and therapeutic response or even desipramine plasma levels.

Depressive Disorder↗

PubMed1989

Desipramine dose prediction based on 24-hour single-dose levels: feasibility and validity.

The authors present a prospective study of a rapid desipramine dose adjustment on the basis of a 24-hour plasma concentration after a single 150 mg dose. For this, they use a prediction table constructed from data in the literature showing strong correlation between steady-state plasma levels and 24-hour single-dose levels. Despite the fact that desipramine action is not always linear, the method appears to be feasible and valid. In an attempt to reach a 150 ng/ml level, the authors obtained steady-state levels ranging from 85 to 317 ng/ml, with 14 of the 19 patients in the range between 125 and 250 ng/ml. Moreover, 11 of the 19 patients received a daily dose of 250 mg or more desipramine from the third day of treatment onward; in ten of these cases, this dose had been adapted.

Adult↗

PubMed1986

Possible nonlinear pharmacokinetics of desipramine after once daily dosing.

Desipramine (DMI) plasma concentrations were measured in depressed outpatients treated with desipramine hydrochloride. Plasma level determinations were measured 24 hours after a single dose of DMI 50 mg, and then at weekly intervals thereafter while receiving once daily bedtime dosing with DMI 150 mg or 200 mg. The 24 hour DMI concentration was significantly, and rather closely correlated with steady state DMI levels (r = 0.74, p less than .001) (prediction coefficient [r2] = 55%). However, steady state plasma levels of DMI were higher than would be predicted based upon prior studies which also examined the relationship between steady state and 24 hour desipramine plasma concentrations. We speculate that the single bedtime administration of DMI in the present study may have led to saturation of metabolic hepatic enzymes during the first pass of the drug through the liver. The possibility of nonlinear DMI pharmacokinetics may be of clinical importance to some patients receiving a single, daily, high dose of medication.

Adult↗

PubMed2002

The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study.

UNLABELLED: The tricyclic antidepressants are often used for the treatment of neuropathic pain. In this study, we evaluated one of these drugs on human cutaneous experimental pain. A randomized, double-blinded, placebo-controlled, crossover design methodology was conducted. Subjects participated in 2 14-day study sessions separated by a 7-day washout period. One session was with desipramine and one with placebo. At baseline, Day 7, and Day 15, quantitative sensory testing was performed to thermal and mechanical stimuli. On Day 15 only, intradermal capsaicin was injected on the volar aspect of the forearm followed by an assessment of pain and hyperalgesia. Oral desipramine had no significant effect on acute sensory thresholds, pain, secondary hyperalgesia, or flare response induced by intradermal capsaicin. Mean peak plasma levels of desipramine were within the therapeutic range for the treatment of depression. This study further supports a lack of effect of the tricyclic antidepressants on acute nociception and experimentally-induced secondary hyperalgesia. IMPLICATIONS: Human experimental pain models have recently been developed; however, the efficacy of the tricyclic antidepressants (TCA) in these models has not been systematically studied. This investigation provides further validation of human experimental pain models and demonstrates that the chronic delivery of a TCA has no effect on human experimental pain.

Adult↗

PubMed1993

Concomitant administration of MK-801 and desipramine enhances extracellular concentration of dopamine in the rat prefrontal cortex.

The interaction between the antidepressant drug desipramine and the non-competitive NMDA receptor antagonist MK-801 was investigated at the level of dopamine release in the rat prefrontal cortex. Peripheral administration of MK-801 (0.2 mg kg-1) or desipramine (10 mg kg-1) evoked weak enhancement of the extracellular dopamine concentration in the rat PFC. Desipramine and MK-801 given jointly in doses which by themselves evoked a mild alteration of dopamine outflow (10 mg and 0.2 mg kg-1 respectively) produced pronounced enhancement of the extracellular concentration of dopamine in the rat prefrontal cortex. It is suggested that the non-competitive NMDA receptor antagonist may enhance the efficacy of classical antidepressant drugs.

Animals↗