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PubMed1986

Effects of desipramine and chlorimipramine on buprenorphine analgesia in mice.

The effects of the tricyclic antidepressants desipramine HCI and chlorimipramine HCI on buprenorphine HCI antinociceptive activity were studied in mice using the hot-plate and the tail-flick methods. In the hot-plate test, desipramine caused a transient antinociceptive effect at low doses, but it decreased buprenorphine analgesia. Chlorimipramine in this test caused a more sustained antinociceptive effect, especially at relatively higher doses, and it did not significantly change buprenorphine analgesia. In the tail-flick test, desipramine either reduced or increased the tail-flick latency in a dose-specific manner, and chlorimipramine (10 mg/kg) significantly increased the tail-flick latency. Desipramine (1 mg/kg) caused a decrease followed by an increase in buprenorphine analgesia. Desipramine (5 and 10 mg/kg) caused significant increases in buprenorphine analgesia. All doses of chlorimipramine (1, 5 and 10 mg/kg) caused significant increases in buprenorphine analgesia. Thus, depending on the test employed, buprenorphine analgesia was modified differently by these tricyclics. Biochemical data suggested a greater role for brain 5-hydroxytryptamine (5-HT) than noradrenaline in tricyclic analgesia.

Analgesics↗

PubMed1994

The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts.

The effect of the tricyclic antidepressant desipramine on the processing of lysosomal sphingomyelinase (EC 3.1.4.12) was investigated by pulse-chase studies on [35S]methionine labeled cultured human skin fibroblasts. Desipramine induced rapid intracellular degradation of mature acid sphingomyelinase when added to the cells in the micromolar range, concomitantly abolishing the enzyme activity. Pulse chase labeling revealed the disappearance of mature enzyme forms when fibroblasts were treated with 25 microM desipramine. Incubation of cells with 25 microM leupeptin, an inhibitor of thiol proteases, 24 h prior to desipramine intoxication prevented this drug-induced effect. From these results we conclude that desipramine and possibly also similarly acting tricyclic antidepressants induce proteolytic degradation of acid sphingomyelinase.

Cells, Cultured↗

PubMed1995

Effects of methylphenidate in HIV-related depression: a comparative trial with desipramine.

This report is a randomized, double-blind, comparative trial of desipramine with the psychomotor stimulant methylphenidate. Twenty HIV antibody-positive patients with depressive symptoms were randomly assigned to either drug. After individual dose titration, the mean daily dose of desipramine was 150 mg. and methylphenidate 30 mg. daily. The differences in responses between desipramine and methylphenidate were not statistically significant on various measures of depression. The antidepressant effect of methylphenidate did not occur any faster than that of desipramine. Both significantly reduced depressive and anxious symptomatology over the blinded portion of the treatments. Thus, methylphenidate relieves depressive symptomatology with efficacy similar to that of desipramine, offering an alternative to patients who are unable to tolerate standard tricyclic antidepressant therapy. The dopaminergic effects of methylphenidate are likely to mediate its antidepressant effects.

Adult↗

PubMed1992

Long term treatment with desipramine increases the turnover of alpha 2-adrenoceptors in the rat brain.

The aim of this study was to quantitate the turnover of alpha 2-adrenoceptors in different regions of the rat brain and its modulation during desipramine (a cyclic antidepressant drug)-induced receptor down-regulation. The recovery of [3H]clonidine (a mixed alpha 2A/B-adrenoceptor agonist) binding after irreversible inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (an alkylating agent for both alpha 2-adrenoceptor subtypes) was assessed in control and desipramine-treated (3 mg/kg, intraperitoneally, every 12 hr for 7-35 days) rats to study the process of alpha 2-adrenoceptor repopulation and to calculate receptor turnover parameters. In control rats, the turnover of brain alpha 2-adrenoceptors showed marked regional differences. The fastest receptor turnover rate was found in the hypothalamus and corpus striatum (receptor half-life, t1/2 = 2.1 days), compared with that in the brainstem (t1/2 = 2.6 days), cerebral cortex (t1/2 = 3.9 days), and hippocampus (t1/2 = 4.3 days). In the cerebral cortex and other brain regions, desipramine induced a time-dependent modulation of alpha 2-adrenoceptors, with significant decreases in the number of receptors (40-71%; p < 0.01) during the first 7-14 days of treatment and regulation to base-line values by 21-35 days. In the cerebral cortex, alpha 2-adrenoceptor turnover evaluated during desipramine-induced receptor down-regulation (phase of 7-14 days of treatment) revealed an increase in both the disappearance (degradation) (delta k = 122%; p < 0.05; t1/2 = 1.7 days) and appearance (synthesis) (delta r = 68%; p < 0.05) rates of the receptor. In other noradrenergic brain regions (hippocampus, brainstem, and hypothalamus) but not in the corpus striatum, desipramine (7-14 days) also increased alpha 2-adrenoceptor degradation (delta k = 97-144%) and shortened the half-life of the receptor, and it tended to increase the rate of synthesis (delta r = 51-83%). Similar results, but with a higher appearance rate, were obtained in the cerebral cortex during the phase of treatment (21-35 days) without apparent receptor down-regulation (delta k = 160%; p < 0.01; t1/2 = 1.5 days; delta r = 128%; p < 0.001). It is proposed that sustained stimulation of alpha 2-adrenoceptors by endogenous norepinephrine, after inhibition of neuronal uptake, increases their disappearance rate (degradation), leading to a reduction in receptor number. The increase in the appearance (synthesis) rate could be viewed as a later compensatory mechanism that would lead to restoration of brain alpha 2-adrenoceptor density.

Adrenergic alpha-Antagonists↗

PubMed1991

2-Hydroxydesipramine and desipramine plasma levels and electrocardiographic effects in depressed younger adults.

Desipramine was given to 34 outpatients aged 20 to 51 years who had primary major depressive disorder but who were otherwise in good health. Daily dosage at bedtime was constant for the final 3 weeks of the 5-week study (mean, [SD] 169.1 [46.1] mg). Electrocardiograms done predrug and after 5 weeks were read by a cardiologist blind to the order in which they were performed. Plasma samples drawn 14 hours after the final study dose were assayed by high performance liquid chromatography; mean (SD) levels were 140.2 (140.0) ng/ml for desipramine and 56.5 (29.4) ng/ml for 2-hydroxydesipramine (2-OH-DMI). Heart rate and PR, QRS and QTc intervals were significantly greater at the end of the study than at baseline, while QT intervals were significantly less. Changes in heart rate and PR, QT and QTc intervals were significantly negatively correlated with the value of the respective cardiac parameters at baseline. Changes in PR interval were significantly positively correlated with log desipramine, log 2-OH-DMI and log (desipramine + 2-OH-DMI). Stepwise multiple regression analyses showed that, for PR interval, each of the three plasma level variables showed a significant ability to improve R2 over that obtained from baseline PR alone. These findings suggest that both 2-OH-DMI and desipramine plasma levels predict a prolongation of intracardiac conduction in younger adults and that monitoring both levels may be useful in the clinical management of certain younger adult patients.

Adult↗

PubMed1990

The role of neuropharmacologic selectivity in antidepressant action: fluvoxamine versus desipramine.

Forty patients with a diagnosis of major depressive disorder were entered in a double-blind study to assess comparative clinical response and pharmacologic parameters of fluvoxamine, a highly selective blocker of serotonin reuptake, and desipramine, a noradrenergic agent. Eighteen patients receiving desipramine and 17 patients receiving fluvoxamine completed the study. Fluvoxamine was comparable to desipramine in its antidepressant efficacy and was better tolerated and caused minimal side effects. There was a direct linear relationship between plasma fluvoxamine levels and clinical response and a nonlinear relationship between plasma desipramine levels and clinical response. The pharmacologic specificity of the two drugs was assessed by determining uptake inhibition of serotonin and norepinephrine. The authors found a positive relationship between Hamilton Rating Scale for Depression scores and norepinephrine uptake inhibition for desipramine but found no such relationship between fluvoxamine and serotonin uptake inhibition. Although there was a clear-cut difference in the quality of pharmacologic specificity and a partial relationship to clinical response, the authors were unable to identify neuropharmacologic factors that would predict either treatment response or selective amelioration of symptomatologies in this patient population.

Adult↗

PubMed1989

The influence of the route of administration of imipramine on imipramine and desipramine blood levels.

Imipramine was used to treat 18 depressed inpatients for 22 days. Imipramine 2 mg/kg/day was administered from day 0 to day 14 intramuscularly, and 4 mg/kg/day was administered orally from days 15-21. Two pharmacokinetic studies were performed, the first at the end of the intramuscular phase (day 14) and the second at the end of the oral phase (day 21). Imipramine and desipramine blood levels were measured every hour from 8 a.m. to 4 p.m. Between these two pharmacokinetic evaluations, blood levels of imipramine and desipramine were measured every morning at 8 a.m. During intramuscular administration, the parent drug imipramine predominated in the plasma and, conversely, the desmethylated metabolite predominated during oral administration. With the changeover in route of administration, the doubling of the dose kept the blood levels of imipramine equal, while desipramine increased; the sum of imipramine and desipramine also increased, and the ratio of imipramine and desipramine decreased sharply, the median ratio changing over 3 days from 1.50 (day 15) to 0.62 (day 18).

Administration, Oral↗

PubMed1984

Use of desipramine in the medically ill.

The use of desipramine in treating major depressive disorder in the hospitalized medically ill patient is described. Desipramine has a low incidence of anticholinergic side effects, causes little orthostatic hypotension, and has a quinidine-like effect on cardiac arrhythmias. Desipramine should be used with caution in patients with risk of heart block and bundle branch block. Guidelines for administration of desipramine in the medically ill are discussed, and drug interactions with medications commonly used in this population are reviewed. Finally, the importance of providing psychotherapy along with desipramine treatment in treating the medically ill depressed patient is emphasized.

Arrhythmias, Cardiac↗

PubMed1993

Fluvoxamine-induced alterations in plasma concentrations of imipramine and desipramine in depressed patients.

The effect of fluvoxamine maleate, 100 mg/day for 10 days, on plasma concentrations of tricyclic antidepressants was studied in 15 depressed patients on maintenance therapy with imipramine (7 pts.) or desipramine (8 pts.). In the subgroup treated with imipramine, plasma levels of imipramine increased significantly (p < 0.001) during fluvoxamine coadministration, while levels of desipramine were not modified. Addition of fluvoxamine to patients on a stable desipramine dosage regimen resulted in a slight, but statistically not significant, increase in desipramine plasma concentrations. These results suggest that fluvoxamine is a potent inhibitor of imipramine demethylation, while it has a weak effect on the hydroxylation of desipramine.

Adult↗

PubMed1993

Fluoxetine and desipramine in major depressive disorder.

The efficacy and safety of fluoxetine and desipramine were compared in a 6-week double-blind, parallel group study of patients with major depression. Twenty-five were studied while hospitalized for treatment, and 33 were studied as outpatients. Improvement on the Hamilton Rating Scale for Depression was significant for both treatments from week 1 through the end of the study and did not differ between the two treatments at any week. Overall, 64% of fluoxetine-treated patients and 68% of desipramine-treated patients had at least a 50% reduction in Hamilton Depression score. We assessed whether improvement relatively early in treatment was predictive of categorical response at 6 weeks. Among fluoxetine-treated patients, but not desipramine-treated patients, the week 3 change in the Hamilton Depression mood item was significantly predictive of the response at 6 weeks. Patients treated with fluoxetine had significantly fewer side effects than those treated with desipramine. Desipramine, but not fluoxetine, caused a persistent increase in heart rate. The results suggest that early signs of response to fluoxetine are not dependent on achieving steady-state levels of the drug.

Adult↗

PubMed1994

Characteristics of desipramine-refractory depression.

BACKGROUND: To determine the predictors of desipramine-refractory depression, the authors examined the outcome in patients with major depression who were admitted to a general hospital and treated with desipramine adjusted to an adequate blood level. METHOD: Sixty-eight consecutive inpatients with DSM-III nonpsychotic unipolar major depression who had failed to respond to 1 week of hospitalization without drug treatment were studied. Outcome was assessed with the Yale Depression Inventory after a 4-week desipramine trial in which 24-hour plasma concentrations were used to rapidly achieve a therapeutic desipramine level. RESULTS: Poor response to a therapeutic desipramine trial, which occurred in 15 of 50 patients, was significantly associated with definite personality disorder, prior treatment failure, near delusional status, age < or = 35 years, duration of depressive episode, recurrence of depression, dysthymia, and secondary depression. The first four items remained significantly correlated with poor response when the presence of the other items was accounted for using multiple regression. Drug response was not predicted by the diagnosis of melancholia (DSM-III and DSM-III-R) or initial severity of the depressive episode. CONCLUSION: The four strongest correlates of outcome were highly predictive of drug response. In patients with two or more predictors, only 25% (4 of 16) responded, while in those with one or no predictors, 91% (31 of 34) responded.

Adult↗

PubMed1978

Imipramine and desipramine in plasma and spinal fluid: relationship to clinical response and serotonin metabolism.

In a double-blind study of depressed patients treated with imipramine hydrochloride, levels of imipramine and desipramine were measured in plasma and in CSF. Levels of both drugs in CSF were approximately 10% of plasma levels, but the levels in the two body fluids were highly correlated. The levels of both drugs were approximately equal in plasma, but desipramine predominated in CSF (imipramine/desipramine ratio of 0.8). The imipramine-induced alteration in CSF levels of the serotonin metabolite (5-hydroxy-indoleacetic acid [5HIAA]) correlated with imipramine levels but not with desipramine. For the group of patients showing a clear antidepressant response, the mean drug levels were nearly double those of the nonresponder group, a difference that did not quite reach statistical significance in this relatively small sample. The desipramine levels showed no responder-nonresponder difference, while the ratio of imipramine/desipramine was significantly higher among the responders. On the average this particular patient group had relatively low pretreatment levels of 5HIAA in CSF, an observation that may partially account for the relatively low overall response rate to imipramine.

Adult↗

PubMed1978

Withdrawal from long-term high-dose desipramine therapy. Clinical and biological changes.

Investigation was undertaken on a patient whose long-term intake of desipramine hydrochloride was amongst the highest reported. Desipramine treatment instituted at a daily dosage of 75 mg for depressive equivalents of head, chest, and abdominal pain was increased to 1,000 mg daily over a 12-year interval with minimal side effects. Plasma desipramine level dropped immediately on withdrawal, and urinary metabolite values dropped over the subsequent five days. The electrocardiographic abnormalities of first-degree atrioventricular block and incomplete left bundle branch block rapidly disappeared on cessation of medication. Electroencephalographic changes with symmetrical generalized irregular 5- to 7-cps theta activity and 18- to 28-cps beta activity also improved. Longitudinal polygraphic sleep studies showed prolonged rapid eye movement rebound and increased delta sleep coincident with withdrawal. It took ten days after cessation of desipramine for urinary 3-methoxy-4-hydroxyphenylglycol concentration to increase substantially. Although catecholamines are involved in growth hormone (GH) and cortisol regulation, no abnormalities were found in GH or cortisol levels.

Adult↗

PubMed1982

Desipramine plasma concentration and antidepressant response.

The relationship of desipramine hydrochloride plasma concentration and antidepressant response was determined in 30 depressed inpatients treated for three weeks with desipramine. All patients had a nondelusional unipolar depression, met DSM-III criteria for major depressive episode with melancholia, and had a Hamilton score of 18 or greater after one week of hospitalization without medication. Eighty-nine percent of the patients with plasma concentrations above 115 ng/mL responded, in contrast to 14% of those with concentrations below this level, a significant difference (Fisher's exact test, P less than .001). Ten initial nonresponders were converted to responders when dosage increase raised desipramine plasma concentration to 125 ng/mL or above. In clinical practice a plasma concentration of 125 ng/mL would be a useful guideline as a threshold above which desipramine is likely to be effective.

Depressive Disorder↗

PubMed1984

Subjective complaints during desipramine treatment. Relative importance of plasma drug concentrations and the severity of depression.

Subjective complaints, including those traditionally considered tricyclic antidepressant side effects, were studied in 43 depressed inpatients during a three-week trial of desipramine hydrochloride. Multiple regression analysis was employed to examine the independent relationship of pretreatment symptoms, concurrent depression, and plasma drug concentrations to subjective complaints reported during treatment. As a group, subjective complaints were positively associated with pretreatment symptoms and the concurrent severity of depression, but not with plasma desipramine concentration. Of the 23 individual complaints studied, three increased during treatment and nine improved. Only two complaints, tremors and light-headedness, were significantly associated with plasma drug concentration. The data indicate that during initial treatment of severe depression with desipramine, subjective complaints are more likely to be symptoms of depression than side effects of the drug and that plasma desipramine determinations would not be useful for predicting or avoiding these complaints. The best management of most symptoms studied was adequate treatment of the depression.

Attitude to Health↗

PubMed1986

Desipramine treatment in normal subjects. Effects on neuroendocrine responses to tryptophan and on platelet serotonin (5-HT)-related receptors.

Normal subjects took the tricyclic antidepressant, desipramine hydrochloride, for 16 days. Following treatment there was an increase in the number of specific binding sites on the platelet for both tritiated imipramine and tritiated LSD, the latter site probably representing a platelet serotonin (5-HT) receptor. During desipramine treatment the prolactin response to tryptophan (L-tryptophan) was enhanced, and this enhancement correlated with the increase in platelet LSD binding. The results confirm previous observations that desipramine administration increases certain 5-HT-mediated neuroendocrine responses. Our findings further indicate that desipramine may alter both 5-HT uptake and 5-HT receptor sensitivity, and suggest that the platelet LSD receptor may in certain conditions provide a useful model of 5-HT receptors in the brain.

Adult↗

PubMed1990

Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine.

To evaluate whether serotonin reuptake inhibition is critical to the treatment of obsessive-compulsive disorder, 40 outpatients with a principal diagnosis of obsessive-compulsive disorder were randomized in a double-blind fashion to 8 weeks of treatment with either the serotonin reuptake inhibitor fluvoxamine maleate (n = 21) or the norepinephrine reuptake inhibitor desipramine hydrochloride (n = 19). Fluvoxamine was significantly better than desipramine in reducing the severity of obsessive-compulsive symptoms, as measured by the Yale-Brown Obsessive Compulsive Scale and by the global response rate ("responder" equaling "much improved"). Eleven of 21 patients were responders with fluvoxamine compared with 2 of 19 patients with desipramine. Fluvoxamine, but not desipramine, was also effective in reducing the severity of "secondary" depression. Fluvoxamine-induced improvement in symptoms of obsessive-compulsive disorder was not correlated with the severity of baseline depressive symptoms. This study provides additional evidence that the acute serotonin reuptake properties of a drug are predictive of its anti-obsessive-compulsive efficacy. It is hypothesized that the mechanism of action of serotonin reuptake inhibitors in obsessive-compulsive disorder may be related to chronic treatment-induced adaptive changes in presynaptic serotonin receptor function (eg, autoreceptor desensitization) and/or indirect influences on dopaminergic function (eg, in the basal ganglia).

Adult↗

PubMed1999

Clomipramine vs desipramine crossover trial in body dysmorphic disorder: selective efficacy of a serotonin reuptake inhibitor in imagined ugliness.

BACKGROUND: Body dysmorphic disorder (preoccupation with an imagined or slight defect in appearance) is a common and disabling disorder associated with high rates of delusional symptoms and suicide attempts. Although preliminary studies suggest that serotonin reuptake inhibitors may be effective for body dysmorphic disorder, to date no controlled treatment studies have been published. METHODS: Forty patients were enrolled and 29 were randomized into a 16-week, double-blind, crossover-design study of clomipramine, a potent serotonin reuptake inhibitor, and active control desipramine, a selective norepinephrine reuptake inhibitor. Outcome measures included specific ratings of body dysmorphic disorder severity, delusionality, and functional impairment. RESULTS: Clomipramine was superior to desipramine in the acute treatment of body dysmorphic disorder symptoms as measured by assessment of patients' obsessive preoccupation with perceived body defects, repetitive behaviors in response to this preoccupation, and global ratings of symptom severity. Treatment efficacy was independent of the presence or severity of comorbid diagnoses of obsessive-compulsive disorder, depression, or social phobia. Likewise, clomipramine was equally effective regardless of whether the patients had insight or held their dysmorphic misperception with delusional intensity. Clomipramine was also superior to desipramine in improving functional disability. CONCLUSIONS: Clomipramine is more effective than desipramine in the treatment of body dysmorphic disorder and is effective even among those patients who are delusional.

Adrenergic Uptake Inhibitors↗