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PubMed1991

Desipramine treatment in panic disorder.

Apart from imipramine (IMI), the efficacy of tricyclic antidepressants in panic disorder (PD) has received surprisingly little investigation. The authors report on a 6 week open trial of desipramine (DMI) preceded by a 10 day placebo lead-in, in 15 patients with PD. By week 6, 80% of the patients were globally rated as much or very much improved on a mean dose of 198 mg. Much of the improvement resulted from a reduction in non-panic attack symptomatology (i.e., psychic, somatic and phobic anxiety). Longer duration of illness, male gender and residual psychic anxiety were associated with poorer response in a subgroup of patients. DMI caused minimal intolerable side effects, suggesting possible compliance advantages in comparison to IMI. Beyond supporting the efficacy of DMI in PD, the results of the study point to a significant medication responsive non-panic illness component and caution against over-relying on panic attacks in assessing both illness severity and treatment response.

Adult↗
PubMed1993

Desipramine does not alter plasma GABA in patients with major depression.

Low plasma GABA is a biological marker for depression in a subset of patients tested. Plasma GABA has been shown to reflect brain GABA activity. This marker has many characteristics of a trait marker for depression, including stability with time, and lack of influence by coincident factors such as gender, season, time, activity or diet. We here report that plasma GABA remained stable after 4 weeks of treatment with desipramine in patients with major depression. Since the levels of plasma GABA did not change with time, nor with clinical improvement, plasma GABA is not a state marker of depression.

Adult↗
PubMed1994

Temperament predicts clomipramine and desipramine response in major depression.

Clinical predictors of drug response in major depression have been weak and inconsistent. Eighty-four patients suffering from a current major depressive episode completed a 6-week double-blind trial of either clomipramine or desipramine. Temperament, as measured by the Tridimensional Personality Questionnaire, accounted for 35% of the variance in treatment outcome, compared with less than 5% predicted by clinical variables. In the more severely depressed patients, temperament predicted nearly 50% of the variance in treatment outcome, which is the first time that such a substantial predictor of drug response has been identified. Within depressed women, temperament also predicted response to different antidepressant drugs. The potential importance of temperament, and the need for replication of these findings is discussed.

Adult↗
PubMed1995

Acute response of social functioning in dysthymic patients with desipramine.

Despite some evidence that short-term antidepressant treatment improves social dysfunction in depressed patients, little is known about the response of specific social impairments in dysthymic patients to antidepressant medication. We examined the effect of acute (10 weeks), open-label desipramine (DMI) treatment on social functioning in subjects with DSM-III-R dysthymia. Social functioning was assessed with the social adjustment scale self-report (SAS-SR) at baseline and at week 10. Compared with DMI nonresponders DMI responders showed significantly greater improvement in overall social functioning (F2,45 = 5.46, P < 0.0001) and in enjoyment of leisure time (F2,45 = 14.38, P < 0.0001) on the SAS-SR. Dysthymic patients who respond to DMI improve significantly in social functioning. Diminished capacity to enjoy leisure time may be a state marker of depression in some chronically depressed patients.

Adult↗
PubMed1996

Interpersonal improvement in chronically depressed patients treated with desipramine.

OBJECTIVE: Interpersonal difficulties of dysthymic patients are little studied. We used the Inventory of Interpersonal Problems (IIP) to assess baseline status and medication response in chronic depression. METHOD: 39 chronically depressed subjects answered the IIP at entry and after 10 weeks of desipramine (DMI). Seventeen DMI responders completed IIPs after a 16-week continuation phase. RESULTS: Mean scores improved on all six IIP subscales during acute treatment. Continuation phase IIP improved non-significantly, approaching normative scores. Baseline IIP score correlated inversely with treatment outcome. CONCLUSIONS: Findings replicate in greater interpersonal detail research demonstrating rapid social amelioration in chronically depressed responders to antidepressant medication. The IIP may be useful as a predictive and interpersonal sensitivity measure in treatment studies of chronic depression.

Adult↗
PubMed1981

Differential effect of chronic desipramine and amitriptyline treatment on rat brain adrenergic and serotonergic receptors.

Serotonergic and adrenergic receptors were examine in rat brains by direct binding assays after chronic treatment with tricyclic antidepressants. Chronic amitriptyline (AMT) treatment (10 mg/kg/day i.p. for 21 days) decreased specific 3H-spiperone binding in the cortex and not in the caudate nuclei. Specific 3H-dihydroalprenolol (3H-DHA) binding was reduced in cerebellar but not in cerebral cortex. Chronic desipramine (DMI) treatment given in the same dose schedule, on the other hand, decreased specific 3H-DHA binding in both cerebellar and cerebral cortex. Specific 3H-spiperone binding in the cerebral cortex was also reduced but to a lesser extent than that in the AMT treated group. Scatchard analysis showed that reductions in 3H-spiperone or 3H-DHA binding in all cases were due to decreases in number of binding sites (Bmax) and not to changes in dissociation constants (KD). No change was observed in 3H-serotonin (3H-5HT), 3H-clonidine, or 3H-WB-4101 binding. The results show that there is no single common change in brain adrenergic and serotonergic receptors after chronic AMT and DMI treatment.

Amitriptyline↗
PubMed1984

Hormonal responses to zimelidine and desipramine in depressed patients.

Plasma prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and cortisol were repeatedly measured during the morning over a 4-hour period in patients who received single or chronic doses of desipramine (DMI) or zimelidine (ZIM). Preclinical studies had suggested that DMI, an uptake inhibitor specific for norepinephrine, would have different effects than ZIM, a selective serotinin uptake inhibitor. The GH response to DMI was blunted in the depressed patients. Neither DMI nor ZIM produced changes in LH or cortisol. DMI acutely increased plasma PRL, whereas ZIM had an effect only after chronic pretreatment. Chronic DMI but not ZIM increased baseline PRL. The patterns and magnitude of responses raise questions concerning the role of serotonin and norepinephrine in PRL release in man and the applicability of current preclinical models.

Adolescent↗
PubMed1985

The cortisol response to desipramine in endogenous depressives and normal controls: preliminary findings.

Plasma cortisol levels were monitored for 2 hours after an intramuscular injection of 75 mg desipramine in 13 endogenous depressives and 20 normal controls. Endogenous depressives had a significantly reduced cortisol response in comparison to normal controls, not explained by sex, age, or baseline cortisol differences between groups. A lack of a cortisol rise of 1.5 micrograms/dl above baseline by 45 minutes discriminated best, with 7 of 13 depressives (55%) being identified in contrast to only 1 of 20 normals (5%). The results suggest that this may be a useful biological test with acceptable sensitivity (55%) and excellent specificity (95%). Furthermore, these data suggest that norepinephrine may be stimulatory to cortisol in man.

Adult↗
PubMed1987

Effects of desipramine and total sleep deprivation on hormonal levels of healthy subjects.

Plasma prolactin (PRL) and growth hormone (GH) were serially measured over a 5-hour morning period in healthy subjects who twice received a single oral dose of 100 mg desipramine (DMI). The study was carried out both after a regular night of sleep and after 1 night of total sleep deprivation. Clinical studies have suggested that sleep deprivation could potentiate the therapeutic effects of antidepressants, and there were reports on DMI stimulation of GH. The basal PRL levels decreased after sleep deprivation, but subsequently increased after DMI, whereas the same dose of DMI did not affect PRL in the absence of after DMI, whereas the same dose of DMI did not affect PRL in the absence of sleep deprivation. The GH levels increased substantially (8- to 10-fold) after DMI in both experimental conditions. Sleep deprivation neither changed GH basal levels nor potentiated the DMI-induced GH increase.

Adult↗
PubMed1988

Desipramine subsensitizes nicotinic mechanism involved in regulating core temperature.

Desipramine HCl, 10 mg/kg i.p. twice daily, produced subsensitivity to the hypothermic effects of nicotine, 1 mg/kg, after 1 and 2 weeks of treatment in male Sprague-Dawley rats, Phenelzine sulfate, fluoxetine HCl, and bright artificial light produced the same effect. The capacity of three chemically distinct classes of anti-depressants and bright artificial light (a treatment for seasonal depression) to produce this result suggests that effects on nicotinic mechanisms may be involved in the mechanism of action of these treatments.

Amitriptyline↗
PubMed1992

Cortisol response to intramuscular desipramine in patients with major depression and normal control subjects: a replication study.

The authors conducted a double-blind study evaluating the cortisol response to 75 mg of desipramine (DMI), administered intramuscularly to 20 patients with major depressive disorder (MDD) and 20 age- and sex-matched normal control subjects. A blunted placebo-corrected cortisol response to DMI was found in MDD patients in comparison with the normal control subjects. Since the behavioral/side effect and pharmacokinetic profiles of DMI were similar for patients with MDD and normal control subjects, these findings suggest that patients with MDD have an underlying biological insensitivity of the hypothalamic-pituitary-adrenal axis to DMI. It is hypothesized that these findings are consistent with a norepinephrine deficit, an alpha 1-adrenergic receptor insensitivity, or both. Further use of DMI as a neuroendocrine probe for the noradrenergic system is indicated.

Adolescent↗
PubMed1993

Effect of desipramine on cerebrospinal fluid concentrations of corticotropin-releasing factor in human subjects.

To assess the effect of desipramine (DMI) on corticotropin-releasing-factor (CRF) activity in the central nervous system, we measured cerebrospinal fluid (CSF) concentrations of CRF in healthy volunteers following short-term administration of DMI or placebo. DMI administration for 2 days was associated with a significant dose-related reduction in CRF concentrations. There was a nonsignificant 6% reduction in CRF concentrations among the 10 subjects who received 50 mg DMI (delta CRF: -3 +/- 2 pg/ml) and a significant 14% fall in the CRF concentrations of the eight subjects who received 100 mg DMI (delta CRF: -8 +/- 3 pg/ml). The mean CSF concentration of CRF was unchanged in the six subjects randomized to placebo (delta CRF: 1 +/- 5 pg/ml). DMI administration had no effect on CSF norepinephrine concentrations (n = 24) or on plasma cortisol (n = 25). We conclude that short-term administration of DMI in healthy volunteers is associated with a dose-related reduction in CSF concentrations of CRF.

Adult↗
PubMed1994

Desipramine-induced increase in norepinephrine transporter mRNA is not mediated via alpha 2 receptors.

In situ hybridization for the norepinephrine transporter (NET) was performed in rats receiving short-term (2 days) treatment with either an alpha-2 (alpha 2) receptor agonist (clonidine) or antagonist (yohimbine) followed by saline or desipramine (DMI). The 'saline' group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of saline. The 'DMI' group received intraperitoneal injections of either clonidine, yohimbine or saline followed by an injection of DMI. Dosages given were clonidine (0.10 mg/kg), yohimbine (0.5 mg/kg) and DMI (10 mg/kg). In the 'saline' group, the clonidine/saline animals had significantly less NET mRNA expression compared to the saline/saline animals. In the 'DMI' group an attentuation of the DMI-induced increase in NET mRNA was observed in the clonidine/DMI animals compared to the saline/DMI animals. In both treatment groups, administration of yohimbine did not alter the expression of NET mRNA compared to the appropriate control animals. These findings suggest that the DMI-induced increase in NET mRNA is not mediated via alpha 2 receptors for, although clonidine attenuates DMI's effect, there is no reciprocal enhancement with the alpha 2 antagonist yohimbine. Clonidine's attenuation of DMI's effect may occur via the imidazole receptor as clonidine is an agonist at the imidazole receptor but yohimbine has no known activity at it. Additional studies are needed to clarify the mechanism of the DMI-induced increase in NET mRNA and to correlate changes in NET mRNA with transporter expression at the synaptic membrane.

Animals↗
PubMed1988

Large scale production and purification of paraquat and desipramine monoclonal antibodies and their Fab fragments.

We describe the rapid, large scale purification of Fab fragments from mouse monoclonal antibodies. Antibodies against two clinically important and often fatal toxins, paraquat and desipramine, were isolated from mouse ascites fluid by preparative high performance hydroxylapatite (HPHT) or ion exchange (DEAE) high performance liquid chromatography. A competitive inhibition ELISA was used to determine the cross-reactivity of the antibody with analogs of the antigens. Papain digests of the IgGs were subjected to further HPHT followed by Sephadex G-100 chromatography to yield homogeneous Fab fragment preparations. The high purity of these preparations, demonstrated by SDS polyacrylamide gel electrophoresis, has only been achieved previously by affinity chromatography. Intrinsic association constants for the intact IgG and the Fab fragment--antigen interactions, determined by competitive inhibition ELISA, were similar. This indicates that antigen-binding activity was conserved during the production and purification of the Fab fragments.

Animals↗
PubMed1991

Drug-specific F(ab')2 fragment reduces desipramine cardiotoxicity in rats.

Current therapy for cardiotoxicity due to tricyclic antidepressant (TCA) overdose is often ineffective in seriously poisoned patients. We studied the effect of a drug-specific antibody fragment on TCA cardiotoxicity in rats. Animals received anti-TCA F(ab')2 2.0 g/kg i.v. over 10 min starting 15 min after administration of a toxic dose of desipramine (DMI). This anti-TCA F(ab')2 dose was 36.9% of the molar DMI dose in terms of binding sites. Anti-TCA F(ab')2 infusion had no adverse effects and rapidly reduced DMI induced QRS prolongation compared with control F(ab')2 (23 +/- 14 vs 71 +/- 11% QRS prolongation at the end of infusion, P less than 0.001). This beneficial effect lasted for the 45 min duration of the study. Markedly enhanced DMI binding in serum after anti-TCA F(ab')2 was demonstrated by a 48-fold increase in the total DMI concentration over controls and a reduction in the fraction of unbound DMI (44.5 +/- 19.4 vs 0.7 +/- 0.2%). Anti-TCA F(ab')2 reduced the DMI concentration in brain but not in other organs. We conclude that anti-TCA F(ab')2 substantially reduces DMI cardiotoxicity in rats, and does so rapidly enough to be of potential clinical benefit for patients with DMI overdose. Because only a small fraction of the DMI dose was bound by antibody, these data suggest that antibody fragment doses considerably less than equimolar to the DMI dose may be effective in treating DMI cardiotoxicity.

Animals↗
PubMed1994

Chronic desipramine treatment influences D1 stimulation and D2 inhibition (dual control) of adenylate cyclase by dopamine in rat striatum.

The response of adenylate cyclase to GTP and to dopamine (DA) was investigated in striatal membranes from desipramine (DMI)- or saline-treated rats. DMI (15 mg/kg) or saline was injected i.p. once a day for 3 weeks. In saline-treated control membranes, GTP exerted a biphasic effect on basal and DA-stimulated enzyme activity; peak levels of stimulation by DA plus GTP were observed at 1 microM GTP. On the other hand, peak levels moved to the right in the GTP dose response curve in DMI-treated membranes. Therefore, D2 inhibition might be attenuated, while the D2 specific agonist, PPHT, was not observed to cause inhibition of adenylate cyclase. Furthermore, D1 stimulation of adenylate cyclase via D1 specific agonist SKF was attenuated in DMI-treated membranes. It seems, therefore, that chronic treatment of rat striatum with DMI exerts a dual influence, that is, a lessening of both D1 stimulation and D2 inhibition of adenylate cyclase, and alters specifically the overall process of the adenylate cyclase system.

Adenylyl Cyclase Inhibitors↗
PubMed1994

Na+,K(+)-ATPase activity in CNS and noradrenergic neurotransmission: time course of differential desipramine (DMI) effects.

ATPase activities in CNS membranes were studied after administration of desipramine (DMI), a noradrenaline (NA) uptake inhibitor. In a previous paper we reported that Na+,K(+)-ATPase activity significantly increased 3 h after DMI administration (10 mg/kg) in hypothalamus and mesencephalus but not in cerebral cortex and pons-medulla oblongata membranes (Viola et al., Cell. molec. Neurobiol. 1989, 9, 263-271). Here it was observed that Na+,K(+)-ATPase increase induced by acute DMI disappeared at 24 h in hypothalamus but remained during 21 days in mesencephalus. Na+,K(+)-ATPase increase by acute DMI was inhibited when endogenous NA was depleted by the noradrenergic neurotoxin DSP-4 or the NA synthesis inhibitor alpha-methyl-p-tyrosine. On the whole, Mg(2+)-ATPase activity was not modified by treatment. 5'-nucleotidase, another membrane-bound enzyme, was unchanged by acute DMI. The addition of DMI in vitro (50 ng/mg tissue) during Na+,K(+)-ATPase assay failed to affect ATPase activities. Acute DMI effects on Na+,K(+)-ATPase are thus attributable to noradrenergic neurotransmission rather than to non-specific drug-CNS membrane interaction. Furthermore, DMI produces differential effects on membrane Na+,K(+)-ATPase, depending on treatment conditions and CNS area studied.

5'-Nucleotidase↗
PubMed1987

Cholinergic properties of desipramine and amoxapine: assessment using a thermoregulation paradigm.

1. The withdrawal of tricyclic antidepressants (TCAs) produces symptoms suggesting cholinergic rebound. 2. Amitriptyline (AMI), the most potent antimuscarinic agent among this class of drugs, produces supersensitivity to the muscarinic agonist, oxotremorine. 3. Enhancement of the sensitivity of cholinoceptive neurons to acetylcholine as a consequence of treatment with TCAs would account for many of the symptoms following the withdrawal of these drugs. 4. Desipramine (DMI) is the least potent antimuscarinic compound among the TCAs, yet its withdrawal produces withdrawal symptoms. 5. Recently, it was reported that amoxapine (AMX) weakly binds to muscarinic acetylcholine receptors (mAchR) in vitro. This may indicate that this drug lacks the effects antimuscarinic effects in vivo, and that it will not supersensitize cholinergic networks. 6. A thermoregulation paradigm was used to assess the sensitivity of a central muscarinic mechanism to oxotremorine before and after treatment with DMI and AMX. Treatment with either drug increased the hypothermic response to this agonist. 7. Mechanisms whereby drugs can produce cholinergic system supersensitivity, and the use of thermoregulation paradigms in assessing the properties of therapeutic agents is discussed.

Amoxapine↗