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PubMed2004

Antidepressant-like effect of tramadol and its enantiomers in reserpinized mice: comparative study with desipramine, fluvoxamine, venlafaxine and opiates.

Tramadol is a centrally acting analgesic that demonstrates opioid and monoaminergic properties. Several studies have suggested that tramadol could play a role in mood improvement. Moreover, it has previously been shown that tramadol is effective in the forced swimming test in mice and the learned helplessness model in rats, two behavioural models predictive of antidepressant activity. The aim of the present study was to test tramadol and its enantiomers in the reserpine test in mice, a classical observational test widely used in the screening of antidepressant drugs. This test is a non-behavioural method where only objective parameters such as rectal temperature and palprebral ptosis are considered. Moreover, we compared the effects of tramadol and its enantiomers with those of antidepressants (desipramine, fluvoxamine and venlafaxine) and opiates [morphine (-)-methadone and levorphanol]. Racemic tramadol, (-)-tramadol, desipramine and venlafaxine reversed the reserpine syndrome (rectal temperature and ptosis), whereas(+)-tramadol and fluvoxamine only antagonized the reserpine-induced ptosis, without any effect on temperature. Opiates did not reverse reserpine-induced hypothermia. (-)-Methadone showed slight effects regarding reserpine-induced ptosis, morphine and levorphanol had no effect. These results show that tramadol has an effect comparable to clinically effective antidepressants in a test predictive of antidepressant activity, without behavioural implications. Together with other clinical and experimental data, this suggests that tramadol has an inherent antidepressant-like (mood improving) activity, and that this effect could have clinical repercussions on the affective component of pain.

Analgesics, Opioid↗

PubMed1981

Plasma concentration monitoring of hydroxylated metabolites of imipramine and desipramine.

Steady-state serum concentrations of imipramine (IMI), its demethylated metabolite desipramine (DMI), and the active, hydroxylated metabolites, 2-hydroxy-imipramine (2-OH-IMI) and 2-hydroxy-desipramine (2-OH-DMI) were monitored in 126 psychiatric patients receiving IMI therapy. DMI and 2-OH-DMI concentrations were determined in a similar group of 61 DMI-treated patients. Although significant correlations exist between hydroxy metabolite and precursor concentrations, considerable variability was also found. Mean (+/- SD) ratios for the IMI patients were: 2-OH-IMI:IMI = 0.27 (+/- 0.19) and 2-OH-DMI:DMI = 0.56 (+/- 0.30). The ratio of DMI:IMI for males and 2-OH-DMI:DMI for females decreased with age (r = -0.42 and -0.32, respectively, p less than 0.01). Variable metabolite concentrations and the uncertainty of their relative psychoactivity may contribute to the difficulties in relating antidepressant efficacy to serum concentrations of the administered IMI or DMI.

Adolescent↗

PubMed1982

Pupil studies in depressed patients: an investigation of the mechanism of action of desipramine.

Six depressed patients were treated routinely with desipramine, a relatively selective noradrenergic uptake blocking drug. After 0, 1 and 3 weeks' treatment, pupillary responses to tyramine, phenylephrine and pilocarpine were measured using a photographic techniques. Both 1 and 3 weeks' treatment significantly inhibited tyramine and phenylephrine-induced mydriasis, but did not inhibit pilocarpine-induced miosis; in fact the longer treatment enhanced miosis due to pilocarpine. Resting pupil size was significantly increased after 1 and 3 weeks' treatment. The findings can be explained by the known ability of desipramine to block noradrenaline uptake and alpha adrenoceptors: they provide no evidence of muscarinic receptor blockade or of a slowly developing adaptation at alpha adrenoceptors.

Adult↗

PubMed1991

A quantitative interresponse-time analysis of DRL performance differentiates similar effects of the antidepressant desipramine and the novel anxiolytic gepirone.

We describe an interresponse-time analysis of performance on a differential-reinforcement-of-low-rate 72-s schedule. This analysis compares the obtained interresponse-time distribution of individual rats to a corresponding random interresponse-time distribution. The random interresponse-time distribution is a negative exponential probability function; it predicts the relative distribution of interresponse times if the rat emitted the same number of responses randomly (i.e., with a constant probability) with respect to time. The analysis provides quantitative measures of peak location and dispersion of the interresponse times toward random performance. In Experiment 1, an unexpected outcome of this analysis was that the rats would have obtained more reinforcers had they responded at the same rate but randomly. Based on the interresponse-time analysis in Experiment 1, it was shown that rats trained on the differential-reinforcement-of-low-rate 72-s schedule could increase the number of reinforcers obtained in two ways: first, by a coherent shift of the interresponse-time distribution toward longer durations and, second, by dispersal of the interresponse times toward a random interresponse-time distribution. Experiment 2 applied the analysis described in Experiment 1 to the effects of desipramine and gepirone. Both drugs decreased response rate and increased reinforcement rate, but their effects on the distribution of interresponse times were different. The increase in reinforcement rate observed with desipramine was accompanied by a coherent shift of the reinforcement rate observed with gepirone was accompanied by dispersal of the interresponse-time distribution toward the random negative exponential prediction.

Animals↗

PubMed1990

Evidence for altered desipramine disposition in methadone-maintained patients treated for cocaine abuse.

Plasma concentrations of desipramine (DMI) and its 2-hydroxy metabolite (OHDMI) were compared among 72 patients being treated with desipramine for either depression (n = 39) or cocaine abuse (n = 33). Eleven cocaine abusers who were concurrently maintained on methadone had a significantly lower ratio of DMI dose to plasma concentration (0.9) than the depressives (2.2) or nonmethadone cocaine abusers (2.0). Their OHDMI/DMI ratios were significantly lower (0.19) than for either the other 22 cocaine abusers (0.39) or the depressed (0.50) patients. This difference was not due to DMI dosage. Although the underlying mechanism cannot be determined from these plasma studies, possible reduced hydroxylation of DMI in methadone patients suggests the need for DMI plasma monitoring.

Adult↗

PubMedDate not supplied

Potentially toxic serum concentrations of desipramine after discontinuation of valproic acid.

Pharmacological interventions in the treatment of various cognitive, behavioural and neurological problems after brain injury often may involve combinations of medications from various drug classes. This carries the implication of potentially new or previously underreported drug interactions. A case report is presented in which a commonly used anticonvulsant drug, valproic acid, and a commonly used antidepressant, desipramine, interacted in such a manner as to cause potentially toxic serum concentrations of desipramine. This case demonstrates the important point that it is not simply the addition of one drug to another that may cause interaction, but the withdrawal of a particular drug which may then adversely impact the remaining drug regimen.

Adult↗

PubMed1992

Treatment of cocaine dependence in methadone maintenance clients: a pilot study comparing the efficacy of desipramine and amantadine.

We conducted a pilot study (N = 22) comparing the efficacy of desipramine and amantadine for treatment of cocaine dependence in methadone maintenance clients. The study which lasted 12 weeks, was double-blind, randomly assigned, and placebo-controlled. Subjects met DSM-III-R criteria for active cocaine dependence. All three groups' cocaine use, craving, and depressive symptoms declined significantly, but intergroup differences were not significant. Clients receiving desipramine were significantly more likely to remain in treatment and to be cocaine free at study completion. The results emphasize the importance of delivering comprehensive services to the cocaine user in methadone treatment. Further evaluations of these two medications as adjuncts in the treatment of cocaine dependence are needed.

Adolescent↗

PubMed1989

Tricyclic antidepressant-specific Fab fragments alter the distribution and elimination of desipramine in the rabbit: a model for overdose treatment.

The effects of tricyclic antidepressant (TCA)-specific Fab fragments (Fab) on total and free desipramine (DMI) levels in serum and urine of DMI-treated rabbits were studied to determine the feasibility of using these Fab for antidotal treatment of TCA overdoses in humans. Serial samples of blood and urine were collected from two 3 kg rabbits after arterial injection of 2 mg 3H-DMI and, about 1.5 hr later, after injection of approximately 1 g Fab (prepared from sheep total IgG). Protein-free filtrates of serum and urine samples were obtained by ultrafiltration; concentrations of apparent total and apparent free DMI (apparent DMI, aDMI = DMI + metabolites) were calculated based on the radioactivity in the sample and ultrafiltrate, respectively. Treatment with Fab induced significant changes in the absolute and relative concentrations of free and total aDMI in both serum and urine. Changes in the serum included increases in the total and free aDMI levels. Changes in the urine included the appearances of a protein-bound aDMI fraction and Fab, and an increase in the percent of unmetabolized DMI. These results demonstrate that TCA-specific Fab influence the distribution and elimination of desipramine in DMI-treated rabbits and suggest that further studies on the use of TCA-specific Fab for antidotal treatment of TCA overdose are warranted.

Animals↗

PubMed1996

Effect of calcium chloride and 4-aminopyridine therapy on desipramine toxicity in rats.

BACKGROUND: Hypotension is a major contributor to mortality in tricyclic antidepressant overdose. Recent data suggest that tricyclic antidepressants inhibit calcium influx in some tissues. This study addressed the potential role of calcium channel blockade in tricyclic antidepressant-induced hypotension. METHODS: Two interventions were studied that have been shown previously to improve blood pressure with calcium channel blocker overdose. CaCl2 and 4-aminopyridine. Anesthetized rats received the tricyclic antidepressant desipramine IP to produce hypotension, QRS prolongation, and bradycardia. Fifteen min later, animals received CaCl2, NaHCO3, or saline. In a second experiment, rats received tricyclic antidepressant desipramine IP followed in 15 min by 4-aminopyridine or saline. RESULTS: NaHCO3 briefly (5 min) reversed hypotension and QRS prolongation. CaCl2 and 4-aminopyridine failed to improve blood pressure. The incidence of ventricular arrhythmias (p = 0.004) and seizures (p = 0.03) in the CaCl2 group was higher than the other groups. CONCLUSION: The administration of CaCl2 or 4-aminopyridine did not reverse tricyclic antidepressant-induced hypotension in rats. CaCl2 therapy may possibly worsen both cardiovascular and central nervous system toxicity. These findings do not support a role for calcium channel inhibition in the pathogenesis of tricyclic antidepressant-induced hypotension.

4-Aminopyridine↗

PubMed1991

Platelet [3H]imipramine and alpha 2-adrenoceptor binding in normal subjects during desipramine administration and withdrawal.

The effect of desipramine 150 mg daily on platelet [3H]imipramine and alpha 2-adrenoceptor binding sites was studied over a 6-week period and for 6 weeks after withdrawal. Modest (10%) increases in [3H]imipramine binding site densities during treatment were noted with a decrease between 1 and 4 weeks after withdrawal. No effect was found on alpha 2-adrenoceptors. Time of day appeared to have some effect on the results found. None of the [3H]imipramine binding site effects of desipramine, on treatment or following withdrawal, was comparable in magnitude to trait differences that were also found between subjects.

Adult↗

PubMed1991

Acute noradrenergic effects of desipramine in depression.

As a probe of the noradrenergic system in depression, single oral doses of the tricyclic antidepressant desipramine (100 mg) and placebo were administered to unipolar and bipolar depressed patients and healthy volunteers. Plasma concentrations of norepinephrine (NE) were determined 2-3 hours after dosing, with subjects in supine and upright positions. On the placebo day plasma NE was low in a subset of bipolar patients; both groups of depressives demonstrated an exaggerated increase in plasma NE upon standing. After desipramine dosing, the orthostatic procedure resulted in even greater relative increments in plasma NE in both patient groups, with no change in volunteers. These data are consistent with noradrenergic dysregulation in depression.

Administration, Oral↗

PubMedDate not supplied

Effect of hypertension and age on alpha 1-adrenoceptors in rat brain: modulation of [3H] prazosin binding by chronic treatment with desipramine and AR-C239.

The influence of repeated treatment with desipramine or AR-C239 on cerebral cortex alpha 1-adrenoceptors of mature (4 months), senescent (24 months) Wistar-Kyoto and mature spontaneously hypertensive rats was measured using [3H] prazosin as a ligand. Chronic desipramine treatment had no effect on [3H] prazosin binding in mature and aged Wistar-Kyoto rats but significantly decreased it in spontaneously hypertensive rats. Repeated AR-C239 treatment did not alter [3H] prazosin binding in senescent Wistar-Kyoto and mature spontaneously hypertensive rats, but significantly increased the [3H] prazosin binding density in mature Wistar-Kyoto rats. Thus, cortical alpha 1-adrenoceptors are not up-regulated by a decreased noradrenergic activity in aged or hypertensive rats as is the case in mature normotensive rats. In addition, these receptors are down-regulated by an increased noradrenergic activity in hypertensive rats only. These results suggest that the synthesis of alpha 1-adrenoceptors is impaired with age or with genetic hypertension and their degeneration is exacerbated with genetic hypertension in response to a changing environment.

Aging↗

PubMed1990

Effects of a chronic administration of the new antidepressant pirlindole on biogenic amine receptors in rat prefrontal cortex and hippocampus. Comparison with desipramine, nomifensine and zimelidine.

Chronic effects of the new antidepressant pirlindole on adrenergic and 5-HT2-receptors in rat prefrontal cortex and hippocampus were investigated in comparison to desipramine, nomifensine and zimelidine. The effects of pirlindole could be clearly distinguished from those of the monoamine reuptake blockers: chronic administration (20 days) of pirlindole (10 mg/kg per day, p.o.) increased prefrontal cortical alpha 2-receptor numbers and did not affect alpha 1-, beta-, and 5-HT2-receptor numbers. In hippocampus its action caused significant increases in alpha 1- and alpha 2-adrenoceptor densities. Administration of the monoamine reuptake blockers desipramine, nomifensine and zimelidine (10 mg/kg per day, p.o.) for 20 days mainly induced reductions of central adrenergic and 5-HT2-receptor numbers. Type-specific increases in monoamine receptor affinities were induced by the four antidepressants investigated, an effect not consistently described in other studies. The results on monoamine receptor numbers and the type specific increases in receptor affinities help to understand the contradiction in binding data versus physiological and behavioural findings.

Animals↗

PubMed1988

Desipramine and cutaneous reactions in pediatric outpatients.

The association of adverse cutaneous effects with administration of the tricyclic antidepressant drug desipramine was systematically reviewed in a clinic population of 205 child psychiatry outpatients over a 3-year period. Transient maculopapular rashes developed in 12 children and adolescents treated with desipramine. The rashes had a benign course, disappearing completely in 2 to 7 days, and were not associated with clinical or chemical hepatitis or any other physical symptoms.

Adolescent↗

PubMed1987

[Desipramine-induced down regulation of beta-adrenergic receptors: effects of noradrenergic and serotonergic neuronal activities and of alpha 2-adrenergic receptor mediated mechanisms].

The mechanisms of antidepressant (desipramine)-induced down regulation of beta-adrenergic receptors were investigated. The number of beta-adrenergic receptors in rat cerebral cortex was increased by the destruction of norepinephrine (NE) neurons with 6-hydroxydopamine or DSP-4 pretreatments. Desipramine (DMI)-induced down regulation of beta-receptors was completely prevented by these procedures, whereas the destruction of serotonin (5-HT) neurons neither changed the receptor number nor prevented the DMI-induced down regulation. The number of beta-adrenergic receptors showed a decrease within 3 days by treatment of DMI plus (+) mianserin or yohimbine which promotes NE and 5-HT release from nerve endings through presynaptic alpha 2-adrenergic antagonism. Another alpha 2-adrenergic antagonist (-)mianserin, which promotes only 5-HT release, also accelerated the down regulation induced by DMI, but this acceleration was not prevented by the destruction of 5-HT neurons. Combination of DMI with 5-HT releasing agent methiothepin (5-HT autoreceptor antagonist) did not accelerate beta-receptor down regulation. These results suggest that 1) NE availability in the synaptic cleft plays a significant role in the regulation of beta-receptor number, but 2) postsynaptic alpha 2-adrenergic mechanisms also seem to contribute to the regulation, whereas 3) 5-HT neurons have no significant effect on the process.

Animals↗

PubMed1987

Biological markers of affective disorders and posttraumatic stress disorder: a pilot study with desipramine.

Three biological markers of affective disorders and response to desipramine were used to study the relationship of posttraumatic stress disorder (PTSD) to affective illness. Blunted TRH response and decreased REM latency in eight patients with PTSD occurred at frequencies similar to those that have been found in patients with major affective disorder. Pretreatment Hamilton Rating Scale for Depression and Beck Depression Inventory scale scores were elevated; scores after 4 weeks' treatment with desipramine revealed significant (p less than .05 and p less than .005, respectively) improvement. These findings support a link between PTSD and affective illness.

Adult↗

PubMed1987

Desipramine plasma levels and clinical response: evidence for a curvilinear relationship.

Twenty-six outpatients with major depression completed a 6-week, fixed dose trial of desipramine and provided plasma samples. Recovery after 6 weeks, defined in either of two ways, corresponded to lower desipramine levels, while clinical status at 4 weeks bore no apparent relationship to plasma levels. Upper limits of 140 or 155 ng/ml emerged depending on the outcome measure used. Patients with endogenous depression, those with primary depression, and those with abnormal dexamethasone suppression test results yielded similar therapeutic thresholds, while the sharpest blood level/response relationship emerged in the subgroup with an abnormal escape from dexamethasone.

Adolescent↗

PubMed1988

Patterns of plasma imipramine-desipramine concentrations in patients receiving concomitant fluphenazine decanoate.

Plasma levels of imipramine and desipramine were monitored in a series of 13 patients with postpsychotic depressions who had a fixed dose of imipramine (150 mg/day) added to their clinically adjusted, stable dose of fluphenazine decanoate. Despite the potential for metabolic inhibition of the tricyclic drug by the neuroleptic drug, no relationship was found between the fluphenazine dose and the subsequent plasma concentrations of imipramine and desipramine. However, plasma antidepressant levels after 1 week at a low dose (50 mg/day) identified patients who later generated high plasma antidepressant levels at the full antidepressant dosage. The clinical implications of these observations are discussed.

Adult↗