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PubMed1993

Effects of trazodone and desipramine on motor recovery in brain-injured rats.

Rats pretrained to walk a narrow balance beam received unilateral sensorimotor cortex lesions, resulting in a contralateral transient paresis that lasted 14 days. In a dose-dependent manner, a single injection of the antidepressant trazodone given 24 hours after injury transiently slowed motor recovery compared with injured controls. After final recovery level of motor function, a reinjection of trazodone reinstated the hemiparesis for up to 6 hours. In other animals, a single injection of the antidepressant desipramine significantly facilitated motor performance when compared with injured controls. Desipramine had no deleterious motor effect when administered to animals that had recovered on the beam-walking task. These findings would suggest that the predominantly noradrenergic neurotransmitter effects of desipramine may facilitate, and those of the predominantly serotonergic trazodone may hinder, the recovery of locomotor performance after cortical injury in rats. Further studies appear indicated, including applying these findings to the clinical setting.

Analysis of Variance↗

PubMed2002

Noradrenergic and serotonergic neuroendocrine responses in prepubertal, peripubertal, and postpubertal rats pretreated with desipramine and sertraline.

OBJECTIVE: To explore whether developmental status of neurotransmitter systems may affect response to antidepressant treatment. This study investigated whether younger animals, compared with mature animals, showed the same neuroendocrine response to challenge drug probes when pretreated with a serotonergic or noradrenergic antidepressant. METHOD: Prepubertal, pubertal, and adult rats were pretreated with low- or high-dose sertraline or desipramine for 14 days. Animals were then challenged with a noradrenergic probe (clonidine for desipramine-treated animals) or a serotonergic probe (fenfluramine for sertraline-treated animals). The neurohormonal response of growth hormone to the clonidine challenge and prolactin to the fenfluramine challenge was then measured. RESULTS: In animals challenged with fenfluramine, the postpubertal control group showed a significantly higher prolactin response to fenfluramine than postpubertal animals pretreated with low- or high-dose sertraline. No differences were found in the pubertal or prepubertal group. In animals challenged with clonidine, there was a significant age by treatment interaction effect for the prepubertal group pretreated with high doses of desipramine (less growth hormone secretion) but not for the peri- or postpubertal groups. CONCLUSIONS: These data indicate neurodevelopmental factors may play a role in the functional physiology of neurotransmitter systems, which in turn may affect response to psychotropics.

Animals↗

PubMed1995

Desipramine treatment of major depression in patients over 75 years of age.

The authors investigated the relationship of desipramine concentrations in plasma to response, side effects, and dose in depressed patients over 75 years of age to determine if these "very old" patients were unusually sensitive to treatment. Thirty-four elderly patients consecutively hospitalized for nonpsychotic, unipolar major depression were treated with a fixed dose desipramine regimen for 4 weeks. Twelve nonresponding patients received a second trial at an increased dose. Comparisons were made with data from younger patients previously published by the authors. At comparable doses, steady-state desipramine concentrations in plasma in the elderly patients did not differ from those observed in younger patients. Response at levels in blood < 115 ng/ml was low, only 6 (21%) of 28 patient trials resulted in response. At levels > or = 115 ng/ml, 6 (46%) of 13 patient trials were effective. These rates were not significantly different. Inspection of the data revealed that a concentration in plasma of 105 ng/ml significantly separated responders and nonresponders (chi 2 = 3.93, df = 1, p < 0.05), but even at levels > or = 105 ng/ml, the response rate was still low relative to rates in prior studies of younger patients treated for a similar duration. The serious adverse reaction rate, 7 of 34, was similar to that previously observed in younger patients. This sample of "very old" elderly was not unusually "sensitive" to antidepressant drug treatment. In fact, the low rate of response observed at usually adequate levels in blood suggested "resistance" to treatment. The findings underscore the need for more effective drug treatments in the depressed elderly.

Aged↗

PubMed1995

Predictors of response to desipramine in dysthymia.

Little is known about factors that may predict the response of dysthymia or other forms of chronic depression to treatment with antidepressant medication. We investigated several sociodemographic and clinical variables for their relationship to the acute treatment response to desipramine in subjects with DSM-III-R dysthymia. Subjects with DSM-III-R dysthymia were treated with desipramine in an open fashion for 10 weeks. Various clinical and sociodemographic variables were assessed at baseline. Ratings of depressive symptoms and severity and determination of categorical outcome were done during treatment. Baseline extended family adjustment as measured by the Social Adjustment Scale Self-Report was significantly better in the responders compared with the nonresponders (2.1 +/- 0.5 vs. 2.6 +/- 0.8; t = 2.84, df = 52.11, p = 0.006). There was a trend (p = 0.06) for overall baseline social impairment (SAS-SR) to be higher in nonresponders versus responders. Older age was a significant predictor of higher depressive severity (Cornell Dysthymia Rating Scale) and global impairment in the last week of the study. No other variable significantly distinguished responders from non-responders. Although few of the variables that were examined were found to affect acute treatment response, better extended family adjustment as reported on the SAS-SR was a significant predictor of good acute treatment response to desipramine in patients with dysthymia.

Adult↗

PubMed1996

Steady-state plasma concentrations of imipramine and desipramine in relation to S-mephenytoin 4'-hydroxylation status in Japanese depressive patients.

The steady-state plasma concentrations of imipramine and desipramine were measured after a more than 2-week treatment with 0.39 to 1.39 mg/kg/day of imipramine hydrochloride in 28 Japanese patients with major depression who had been phenotyped simultaneously with mephenytoin (for CYP2C19-related status) and with metoprolol (for CYP2D6-related status) before initiating the antidepressant therapy. Patients consisted of five poor metabolizers (PMs) of CYP2C19 with an extensive metabolizer (EM) phenotype of CYP2D6, whereas the remainder were EMs for both of the phenotypes. The mean respective concentrations (corrected by mg/kg) of imipramine and the sum of imipramine plus desipramine were 2.4 and 1.8 times greater in the CYP2C19-related PM than in the EM group, and these two variables correlated with the log10 urinary excretion of 4'-hydroxymephenytoin (rs = -0.73 and -0.64, both p < 0.01, respectively), but not with the metabolic ratio (MR) of metoprolol/alpha-hydroxymetoprolol. The mean N-demethylation index (MR of desipramine/imipramine) was significantly (p < 0.01) less in the PM than in the EM group. This index correlated with the 4'-hydroxylation of S-mephenytoin (rs = -0.51, p < 0.01), but not with the alpha-hydroxylation of metoprolol, implying that imipramine N-demethylation is under a coregulatory pharmacogenetic control of CYP2C19, but not of CYP2D6. In conclusion, by taking into account that the incidence of the PMs of CYP2C19 is much greater (18-23%) than that of CYP2D6 (< 1%) in Japanese population, the individually predetermined assessment of the CYP2C19-mediated metabolic capacity of imipramine would be more valuable than that of the CYP2D6-mediated capacity for forecasting the steady-state concentrations of imipramine and desipramine in Japanese depressive patients, thereby attaining an individualized optimization of imipramine therapy. Obviously, a pharmacodynamic assessment study conducted simultaneously with predetermined CYP2C19 status is required for supporting this contention.

Adult↗

PubMed1997

Desipramine versus phenelzine in recurrent unipolar depression: clinical characteristics and treatment response.

We compared desipramine with phenelzine in a double-blind, parallel-groups study of 43 outpatients with recurrent unipolar depression. Response to the two drugs was similar, with an overall average reduction in scores on the Hamilton Rating Scale for Depression of about 50% over 6 weeks. Improvement was negatively correlated with initial severity of depression, especially in patients treated with desipramine. Response to desipramine was better in patients with moderate to severe stressors and no previous hospitalizations. Response to either treatment was better in patients whose course consisted of recurrent depressions with a stable baseline, even if the baseline was dysthymic.

Adolescent↗

PubMed1990

A controlled trial of adinazolam versus desipramine in geriatric depression.

Thirty outpatients between the ages of 60 and 85 with DSM-III Major Depression entered an 8 week randomized, double-blind comparison of desipramine and adinazolam mesylate, a triazolobenzodiazepine derivative. Outcome was assessed on several measures including the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Rating Scale, Clinical Global Impressions (CGI), the 35-item Self-Rating Symptom Scale, and Carroll Depression Scale. Patients in both groups demonstrated a highly significant decrease in average HDRS scores (p less than 0.001) over the course of the study. Adinazolam was associated with significantly greater reduction in average HDRS scores by the third day. Repeated measures analysis of variance showed a significantly greater reduction in HDRS scores for adinazolam over the course of the study. The study medications were associated with distinct patterns of adverse reactions. Desipramine more often produced dry mouth, constipation and nervousness, while adinazolam was more likely to cause drowsiness and lightheadedness. Three of these elderly patients, all of whom were taking desipramine reported at least one fall during the study. Adinazolam may be a promising agent in the treatment of depression in the elderly.

Administration, Oral↗

PubMed1995

Premenstrual syndrome: a double-blind controlled trial of desipramine and methylscopolamine.

The aim of this study was to compare the effect of the selective noradrenergic reuptake inhibitor desipramine and methylscopolamine bromide, a parasympatholytic agent, on late luteal phase dysphoric disorder (LLPDD), or premenstrual syndrome (PMS), as defined in DSM-III-R. Fourteen patients with PMS were assessed both retrospectively and prospectively during premenstrual cycles. All met the DSM-III-R criteria for LLPDD. They received 3 months treatment each with both desipramine and methylscopolamine in random order using a double-blind cross-over design. PMS symptomatology was significantly reduced after treatment with desipramine and methylscopolamine bromide compared with baseline, but there was no significant difference between them in efficacy. There is evidence from this study that both anticholinergic and noradrenergic pathways may be involved in the genesis of PMS.

Adolescent↗

PubMed1990

Increased sensitivity to noradrenaline in glucocorticoid-treated rats: the effects of indomethacin and desipramine.

Vascular responsiveness was evaluated in perfused mesenteric arteries from rats infused with dexamethasone (2 micrograms/day). Full dose-response curves to noradrenaline, vasopressin and potassium chloride were established. In order to investigate whether prostaglandins or noradrenaline uptake were involved in dexamethasone-induced pressor changes, vascular responses were compared before and during treatment with either indomethacin (a cyclo-oxygenase inhibitor) or desipramine (an inhibitor of neuronal catecholamine uptake). Dexamethasone-treated tissues showed an increased vascular sensitivity to noradrenaline compared with controls; the maximal response was greater and the concentrations of agonist required for a 50% response (EC50) was less in dexamethasone-treated tissues. The responses to vasopressin and potassium chloride were not affected. Systolic blood pressure in dexamethasone-treated rats was not significantly different from that in controls. Indomethacin infusion decreased the vascular responsiveness to noradrenaline in control and dexamethasone-treated rats to a similar degree. Noradrenaline responses after indomethacin treatment were not significantly different in control and dexamethasone-treated tissues. 6-Keto-prostaglandin-F1 alpha output during stimulation with noradrenaline was not affected by dexamethasone. Desipramine lowered pressor responses to noradrenaline at all concentrations and decreased the maximal response in tissues from dexamethasone-treated but not control rats. However, during infusion with desipramine, the EC50 for noradrenaline after dexamethasone was still less than in controls. Dexamethasone at low doses appears to selectively increase vascular sensitivity to noradrenaline in rats at a prehypertensive stage by changing prostaglandin synthesis and, possibly, neuronal uptake of noradrenaline.

Animals↗

PubMedDate not supplied

Effect of desipramine on propranolol-induced diminution of noradrenaline release by nerve stimulation.

In atria from rats killed 1 h after either chronic parenteral (daily subcutaneous injections of 5 mg/kg/day for 15 days) or prolonged oral administration of (-)-propranolol (1 mg/ml ad libitum during 15 days) there was a 50% decrease in the overflow of [3H]noradrenaline ([3H]NA) elicited by cardioaccelerans nerve stimulation at 2 Hz, as previously reported for the in vitro exposure of guinea pig atria to propranolol. The chronotropic responses to nerve stimulation and to isoprenaline were also significantly reduced. On the other hand, 40 h after the last injection of propranolol, the overflow of [3H]NA induced by stimulation was still reduced to 50% of the control values, whereas no blockage to nerve stimulation or to isoprenaline was observed. Neither the basal output of [3H]NA nor the tissue levels of the endogenous transmitter were modified by any of the treatment schedules applied. In a separate set of experiments performed in isolated guinea pig atria stimulated at 4 Hz during 1 min, the in vitro exposure to 0.5 microM desipramine prevented the 30% decrease in the overflow of [3H]NA caused by 0.1 microM (-)-propranolol. Desipramine, by itself, did not modify the overflow of the transmitter. It is concluded that propranolol, both in vitro and after chronic in vivo treatments, reduces the overflow of [3H]NA in response to nerve stimulation. The fact that the in vitro effect of the beta-blocker is antagonized by desipramine suggests that propranolol may have to be taken up by the nerve terminals in order to exert its presynaptic inhibition on the release of noradrenaline.

Adrenergic beta-Antagonists↗

PubMed1993

Effect of fluvoxamine on the pharmacokinetics of imipramine and desipramine in healthy subjects.

The effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine caused a significant prolongation of imipramine half-life (from 22.8 +/- 6.4 to 40.5 +/- 5.0 h, means +/- SD, p < 0.01) and a marked decrease in imipramine apparent oral clearance (from 1.02 +/- 0.19 to 0.28 +/- 0.06 L/h/kg, p < 0.0001). No significant changes in desipramine kinetics were observed during fluvoxamine treatment. These findings indicate that, at the dosage tested, fluvoxamine markedly inhibits the demethylation of imipramine without affecting significantly the CYP2D6-mediated hydroxylation of desipramine.

Adult↗

PubMed1994

Immunoassay reagents for psychoactive drugs. Part 5. Quantitative determination of imipramine and desipramine by fluorescence polarization immunoassay.

Two methods for the quantitative determination of imipramine (IMI) and desipramine (DMI) by fluorescence polarization immunoassay (FPIA) are described. One immunoassay allows for the accurate quantification of imipramine in the presence of desipramine, while the other allows for the accurate quantification of desipramine in the presence of imipramine.

Chromatography, High Pressure Liquid↗

PubMed1986

Desensitization of beta-adrenergic receptor-coupled adenylate cyclase in cerebral cortex after in vivo treatment of rats with desipramine.

Continuous treatment (1-10 days) of rats with desipramine (10 mg/kg, twice per day) caused desensitization of the beta-adrenergic receptor-coupled adenylate cyclase system of cerebral cortical membranes. The decrease in the isoproterenol-stimulated adenylate cyclase activity was more rapid and greater than the decrease in the number of beta-adrenergic receptors in membranes during treatment of the membrane donor rats with desipramine, indicating that the desensitization occurring at an early stage of the treatment was not accounted for solely by the decrease in the receptor number. Neither the guanine nucleotide regulatory protein (N) nor the adenylate cyclase catalyst was impaired by the drug treatment, since there was no decrease in the cyclase activity measured in the presence or absence of GTP, guanyl-5'-yl-beta-gamma-imidodiphosphate [Gpp(NH)p], NaF, or forskolin. Gpp(NH)p-induced activation of membrane adenylate cyclase developed with a lag time of a few minutes in membranes from control or drug-treated rats. The lag was shortened by the addition of isoproterenol, indicating that beta-receptors were coupled to N in such a manner as to facilitate the exchange of added Gpp(NH)p with endogenous GDP on N. This effect of isoproterenol rapidly decreased during the drug treatment of rats. Thus, functional uncoupling of the N protein from receptors was responsible for early development of desensitization of beta-adrenergic receptor-mediated adenylate cyclase in the cerebral cortex during desipramine therapy.

Adenylyl Cyclases↗

PubMed1993

Repeated administration of desipramine and a GABAB receptor antagonist, CGP 36742, discretely up-regulates GABAB receptor binding sites in rat frontal cortex.

1. GABAB receptor binding site densities within laminar regions of the rat frontal cortex were examined autoradiographically following repeated administration (21 days) of the antidepressants desipramine, paroxetine and amitriptyline in addition to the GABAB receptor antagonists, CGP 35348 and CGP 36742. beta 1-Adrenoceptor autoradiography was studied in parallel with that for GABAB receptor sites. 2. The effects of these compounds were examined concomitantly on the GABAB receptor-mediated inhibition of forskolin- and enhancement of noradrenaline-stimulated cyclic AMP production. 3. GABAB receptor binding was increased by both desipramine (20 mg kg-1, p.o. and 10 mg kg-1, i.p.) and CGP 36742 (100 mg kg-1, i.p.) in the outer laminar region of the frontal cortex by around 50% above control levels. Conversely, no significant changes were mediated by paroxetine, amitriptyline, CGP 35348 or the GABAB receptor agonist, baclofen. 4. With the exception of paroxetine, all compounds down-regulated the total beta-adrenoceptor population throughout frontal cortical laminae which was attributable to the beta 1-adrenoceptor subtype. In contrast, the reduction in beta-adrenoceptors mediated by CGP 35348 and CGP 36742 did not occur as a consequence of reduced beta 1-adrenoceptor numbers. 5. Protracted treatment with CGP 35348, failed to influence forskolin-stimulated cyclic AMP production; however, a significant increase in the accumulation of cyclic AMP produced in response to forskolin was seen after treatment with CGP 36742. 6. Such discretely localized changes in GABAB receptor densities induced by desipramine and CGP 36742 may provide an explanation for the discrepancies reported in membrane binding studies and possibly implicate a role for GABAB receptor antagonists in antidepressant therapy.

Adenylyl Cyclases↗

PubMed1982

Antidepressant effect of femoxetine and desipramine and relationship to the concentration of amine metabolites in cerebrospinal fluid. A double-blind evaluation.

The antidepressant and biochemical effects of femoxetine, a selective serotonin uptake inhibitor, and desipramine, a selective nor-adrenaline uptake inhibitor, have been compared in a double-blind study in 42 outpatients with depressive illness. The patients were allocated at random to treatment with either 600 mg femoxetine or 150 mg desipramine daily for 6 weeks. The total depression score showed a significant decrease in both groups, indicating an overall improvement in depressive symptoms. The patients treated with femoxetine reported significantly less severe anticholinergic effects during the whole treatment period than the desipramine patients. Both drugs, decreased the level of 5-HIAA in CSF, whereas no consistent changes were found in the MHPG and HVA levels. The pretreatment level of the metabolites had no predictive value for the outcome of the treatment with either drug. No significant correlation was found between therapeutic effect and the plasma concentration of the active compounds.

Adult↗

PubMed1983

A double-blind comparison of zimelidine and desipramine in endogenous depression.

Zimelidine, a specific 5HT uptake inhibitor (final dose 225 mg), and desipramine, mainly a noradrenaline uptake inhibitor (final dose 150 mg), were given in random order to 24 in- and out-patients fulfilling the Research Diagnostic Criteria for Major Depressive Disorder, definite or probable endogenous type, for a 3-week treatment period. Nonresponders were crossed over to the other drug for another 3 weeks. There was a nonsignificant trend towards more overall improvement on desipramine. Some patients in both groups showed very little change during 3 weeks, indicating a bimodal distribution of response to either drug. Several nonresponders improved markedly upon direct crossing over to the other drug. There were few and mild side effects on both drugs, with no significant difference between them. No significant correlation was found between improvement and plasma concentrations of zimelidine, norzimelidine, or desipramine, whereas a significant positive correlation was found between improvement and platelet serotonin uptake inhibition (measured in fresh platelets incubated in diluted plasma from the patients) in zimelidine-treated patients.

Adolescent↗

PubMed1988

Early postnatal deprivation of active sleep with desipramine or zimeldine impairs later behavioural reactivity to auditory stimuli in rats.

To examine the functional significance of early postnatal active sleep for the development of behavioural reactivity to auditory stimuli, rat pups were daily injected i.p. from the 7th to the 18th postnatal days with 5 mg kg-1 (6.6 mmol l-1) desipramine or 25 mg kg-1 (12.2 mmol l-1) zimeldine. Sleep-wake behaviour was recorded with a static-charge-sensitive bed (SCSB) method. Both desipramine and zimeldine suppressed the percentage of active sleep relative to the total recording time throughout the treatment period. In addition, these drugs increased the percentage of quiet state and waking. At the age of 38 days the zimeldine-treated rats showed more motor activity in the open field than the controls. At the age of 39 and 78 days all rat groups behaved similarly in the open field. Startle measures and motor activation, provoked by auditory stimulation, were determined by the SCSB method when the rats were 4 months of age. Auditory stimuli, consisting of a series of ten clicks, induced a greater number of startles as well as strong movement responses in the control rats than in the desipramine- or zimeldine-treated rats. The number of small movement responses did not differ between the rat groups. These findings indicate that early postnatal active sleep and the monoaminergic systems regulating it may be important for the normal development of neuronal circuitry associated with later reactivity to auditory stimuli.

Acoustic Stimulation↗

PubMed1983

Stereoselectivity of catecholamines: differential effects of cocaine and desipramine on catecholamine-induced contractions of the rat isolated vas deferens.

The effect of uptake inhibitors, cocaine and desipramine, on the contractile response of the rat isolated vas deferens to the enantiomers of noradrenaline and adrenaline and to the corresponding deoxy-derivatives, dopamine and epinephline, was investigated. Cocaine (10(-6)M) significantly potentiated all six agonists; the effect was most marked for the laevo-isomers (-)-noradrenaline and (-)-adrenaline. Desipramine (10(-7) M) also potentiated (-)-noradrenaline, (+)-noradrenaline, (-)-adrenaline, (+)-adrenaline and epinephline but, in contrast, antagonized dopamine. This selective antagonism of dopamine by desipramine was also observed for the separated epididymal and prostatic ends of the rat vas deferens.

Animals↗