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Behavioural Brain Research Aug 2017Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the...
Deficits in neuronal inhibition via gamma-aminobutyric acid (GABA) type A receptors (GABAA-Rs) are implicated in the pathophysiology of major depressive disorder and the therapeutic effects of current antidepressant treatments, however, the relevant GABAA-R subtype as defined by its alpha subunit is still unknown. We previously reported anxiety- and depressive-like behavior in alpha2+/- and alpha2-/- mice, respectively (Vollenweider, 2011). We sought to determine whether this phenotype could be reversed by chronic antidepressant treatment. Adult male mice received 4 or 8mg/kg fluoxetine or 53mg/kg desipramine in their drinking water for four weeks before undergoing behavioral testing. In the novelty suppressed feeding test, desipramine had anxiolytic-like effects reducing the latencies to bite and to eat the pellet in both wild-type and alpha2+/- mice. Surprisingly, 4mg/kg fluoxetine had anxiogenic-like effects in alpha2+/- mice increasing latency to bite and to eat while 8mg/kg fluoxetine increased the latency to eat in both wild-type and alpha2+/- mice. In the forced swim and tail suspension tests, chronic desipramine treatment increased latency to immobility in wild-type and alpha2-/- mice. In contrast, chronic fluoxetine treatment increased immobility in alpha2-/- mice in both tasks while generally having no effect in wild-type mice. These findings suggest that in preclinical paradigms of anxiety and behavioral despair the antidepressant-like effects of desipramine are independent of alpha2-containing GABAA-Rs, while a reduction in alpha2 expression leads to an increased sensitivity to anxiogenic- and prodepressant-like effects with chronic fluoxetine treatment, pointing to a potential role of alpha2-containing GABAA-Rs in the response to serotonin-selective antidepressants.
Topics: Adrenergic Uptake Inhibitors; Animals; Antidepressive Agents; Anxiety; Depression; Desipramine; Dose-Response Relationship, Drug; Feeding Behavior; Fluoxetine; Male; Mice, 129 Strain; Mice, Knockout; Motor Activity; Phenotype; Receptors, GABA-A; Selective Serotonin Reuptake Inhibitors
PubMed: 28587819
DOI: 10.1016/j.bbr.2017.05.063 -
British Journal of Clinical Pharmacology Nov 19901. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double-blind, randomised, placebo controlled, cross-over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day-1 and 200 mg desipramine day-1 whereas poor metabolisers were treated with 50 mg day-1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70-510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130-910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer- and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl-clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.
Topics: Adult; Aged; Clomipramine; Desipramine; Diabetic Neuropathies; Double-Blind Method; Drug Evaluation; Female; Humans; Male; Middle Aged; Phenotype; Sparteine
PubMed: 2271367
DOI: 10.1111/j.1365-2125.1990.tb03836.x -
Drug Metabolism Letters Dec 2009Desipramine (DMI), a CYP2D6 probe, was used as a model drug to test whether CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice could be used as preclinical animal... (Comparative Study)
Comparative Study
Desipramine (DMI), a CYP2D6 probe, was used as a model drug to test whether CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice could be used as preclinical animal models to identify the effects of CYP2D6 genotype/phenotype on drug metabolic profiles. After the analyses by liquid chromatography coupled with tandem mass spectrometry, DMI biotransformations were compared in Tg-CYP2D6 and wild-type mouse liver microsomes (MLM), and in human CYP2D6 extensive and poor metabolizer liver microsomes. Furthermore, urinary DMI metabolic profiles in Tg-CYP2D6 and wild-type mice were evaluated. Three metabolites, 2-hydroxyl-, 10-hydroxyl, and N-desmethyl-desipramine were identified in the incubations of DMI with both wild-type and Tg-CYP2D6 MLM, as well as in human CYP2D6 extensive metabolizer liver microsomes. Three additional metabolites were found in mouse urine samples, and their chemical structures were elucidated. Although the ratio of individual metabolites produced in Tg-CYP2D6 MLM was closer to that in human CYP2D6 extensive metabolizer liver microsomes, the urinary DMI metabolic profiles did not show much difference between wild-type and Tg-CYP2D6 mice. The results suggest that other mouse enzymes have significant contribution to DMI metabolism.
Topics: Animals; Antidepressive Agents, Tricyclic; Chromatography, Liquid; Cytochrome P-450 CYP2D6; Desipramine; Genotype; Humans; In Vitro Techniques; Mice; Mice, Transgenic; Microsomes, Liver; Models, Animal; Polymorphism, Genetic; Tandem Mass Spectrometry
PubMed: 19995332
DOI: 10.2174/187231209790218118 -
The Journal of Pain Nov 2005In 47 patients with postherpetic neuralgia (PHN) who had never had an adequate trial of any antidepressant, we performed a randomized, double-blind, parallel design... (Comparative Study)
Comparative Study Randomized Controlled Trial
UNLABELLED
In 47 patients with postherpetic neuralgia (PHN) who had never had an adequate trial of any antidepressant, we performed a randomized, double-blind, parallel design trial comparing desipramine, amitriptyline, and fluoxetine. Patients were titrated to a maximum of 150 mg/day for desipramine and amitriptyline and 60 mg/day for fluoxetine over a 3-week period and then treated for an additional 3 weeks before tapering off study medication. A total of 38 subjects (81%) completed the entire trial. The modified intent-to-treat analysis of percent change in daily diary pain intensity scores showed no significant differences among the 3 drugs (ANOVA P = .120). Desipramine produced the greatest reduction in pain intensity (47%), followed by amitriptyline (38%) and fluoxetine (35%). Clinically meaningful pain relief (moderate or better) was significantly more likely with desipramine (12/15 patients) than with amitriptyline (9/17) or fluoxetine (5/15); chi(2)P = 0.036). The 11 subjects using opioids at study entry had smaller reductions in pain than those not using concomitant opioids. The fluoxetine group had the highest noncompletion rate (33%), with 1 subject hospitalized for hyponatremia. Although the magnitude of pain reduction and the category pain relief rating was not significantly different among the 3 drugs, the tricyclics desipramine and amitriptyline were well tolerated and provided clinically meaningful pain relief in 53% to 80% of subjects.
PERSPECTIVE
Few clinical trials focus on patients who are naïve to an entire class of medication. In this randomized blinded trial, the tricyclic antidepressants desipramine and amitriptyline were compared to the serotonin-selective antidepressant fluoxetine. All 3 drugs reduced PHN pain, with desipramine providing satisfactory relief in 80% of those treated.
Topics: Adult; Aged; Aged, 80 and over; Amitriptyline; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Desipramine; Double-Blind Method; Female; Fluoxetine; Humans; Male; Middle Aged; Neuralgia, Postherpetic; Patient Dropouts; Treatment Outcome
PubMed: 16275598
DOI: 10.1016/j.jpain.2005.07.001 -
Pharmacological Reports : PR 2013Antidepressant drugs, like fluoxetine, a selective serotonin reuptake inhibitor, desipramine, a nonselective noradrenaline reuptake inhibitor, and mirtazapine, an...
BACKGROUND
Antidepressant drugs, like fluoxetine, a selective serotonin reuptake inhibitor, desipramine, a nonselective noradrenaline reuptake inhibitor, and mirtazapine, an antagonist of noradrenaline α2 auto- and heteroreceptors, are widely used for the treatment of depressive symptoms in cancer patients. Since these antidepressants have different activities targeting the immune system, they might also modulate tumor growth in cancer patients.
METHODS
In the present study, we investigated the effects of administration of antidepressant drugs: fluoxetine, desipramine and mirtazapine on B16F10 melanoma tumor growth. These drugs were administered intraperitoneally (ip) for 17 days after subcutaneous injection of B16F10 melanoma cells to male C57BL/6J mice.
RESULTS
Fluoxetine significantly inhibited melanoma solid tumor growth and desipramine tended to decrease this parameter whereas mirtazapine had no effect.
CONCLUSION
The inhibitory effect of fluoxetine on melanoma growth was associated with an increased mitogen-induced T cell proliferation which may at least partly participate in the mechanism of the antitumor effect of this antidepressant. It appears that the inhibitory effect of fluoxetine on tumor growth is not related with changes in cytokine levels except for IL-10.
Topics: Animals; Antidepressive Agents; Cell Proliferation; Desipramine; Fluoxetine; Interleukin-10; Male; Melanoma, Experimental; Mianserin; Mice; Mice, Inbred C57BL; Mirtazapine; T-Lymphocytes; Tumor Cells, Cultured
PubMed: 23950590
DOI: 10.1016/s1734-1140(13)71045-4 -
International Journal of Molecular... Apr 2017Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid...
Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients' mortality. Acid sphingomyelinase (SMPD1)-the principal regulator for rapid and transient generation of the lipid mediator ceramide-is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1 as well as SMPD1 animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1 littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine.
Topics: Animals; Biomarkers; Cardiac Output; Ceramides; Desipramine; Disease Models, Animal; Female; Gene Expression Profiling; Gene Expression Regulation; Heart Diseases; L-Lactate Dehydrogenase; Lipid Metabolism; Male; Mice; Mice, Knockout; Mice, Transgenic; Myocardium; Oxidative Stress; Sepsis; Sphingomyelin Phosphodiesterase; Troponin I
PubMed: 28420138
DOI: 10.3390/ijms18040839 -
Biosensors Jan 2023In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs),...
On-Chip Electromembrane Surrounded Solid Phase Microextraction for Determination of Tricyclic Antidepressants from Biological Fluids Using Poly(3,4-ethylenedioxythiophene)-Graphene Oxide Nanocomposite as a Fiber Coating.
In the present study, on-chip electromembrane surrounded solid phase microextraction (EM-SPME) was employed in the determination of tricyclic antidepressants (TCAs), including amitriptyline, nortriptyline, imipramine, desipramine, maprotiline, and sertraline, from various biological fluids. In this regard, poly(3,4-ethylenedioxythiophene)-graphene oxide (PEDOT-GO) was electrodeposited on an SPME fiber as a conductive coating, then the fiber played the acceptor-electrode role during the extraction. Thus, the immigration of the analytes under the influence of an electric field and their absorption onto the fiber coating were accomplished simultaneously. Under the optimized conditions, the limits of detection for the target analytes were acquired in the range of 0.005-0.025 µg L using gas chromatography-mass spectrometry. The linearity of the method was 0.010-500 µg L for the imipramine and sertraline, 0.025-500 µg L for the amitriptyline, nortriptyline, and desipramine, and 1.000-250 µg L for the maprotiline (R ≥ 0.9984). Moreover, this method provided suitable precision and fiber-to-fiber reproducibility, with RSDs ≤ 8.4%. The applicability of the proposed setup was eventually investigated for extraction of the drugs from human bone marrow aspirate, urine, plasma, and well water samples, in which satisfactory relative recoveries, from 93-105%, were obtained.
Topics: Humans; Antidepressive Agents, Tricyclic; Amitriptyline; Nortriptyline; Imipramine; Solid Phase Microextraction; Desipramine; Sertraline; Maprotiline; Reproducibility of Results; Nanocomposites; Limit of Detection
PubMed: 36671973
DOI: 10.3390/bios13010139 -
Journal of Psychiatric Research Jul 2008To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we... (Comparative Study)
Comparative Study
To study the delay (2-6 weeks) between initial administration of norepinephrine reuptake inhibitor antidepressants and onset of clinical antidepressant action, we examined the effects of desipramine treatment on urinary and plasma catecholamines and their metabolites during the initial 6 weeks of treatment in depressed patients. Catecholamines and metabolites in 24-h urine collections and 8:00 a.m. plasma samples were measured at baseline and after 1, 4, and 6 weeks of desipramine treatment. Desipramine treatment produced significant increases in urinary norepinephrine (NE) and normetanephrine (NMN) and plasma NE at Weeks 4 and 6, but not at Week 1. The ratio of urinary NE/NMN was increased at Weeks 4 and 6, suggesting a reduction in the metabolism of NE to NMN at extraneuronal sites by Weeks 4 and 6. The increases in urinary NE and NMN and plasma NE at Weeks 4 and 6 of desipramine treatment were associated with a reduction in the conversion of NE to NMN. This would be compatible with a blockade of the extraneuronal monoamine transporter (organic cation transporter 3; SLC22A3) by NMN. Inhibition of the extraneuronal monoamine transporter may be an important component in the clinical pharmacology of the norepinephrine reuptake inhibitor antidepressant drugs, such as desipramine.
Topics: Adrenergic Uptake Inhibitors; Adult; Catecholamines; Depressive Disorder; Desipramine; Female; Humans; Male; Middle Aged; Monoamine Oxidase; Norepinephrine; Normetanephrine; Organic Cation Transport Proteins; Receptors, Adrenergic, alpha-2
PubMed: 17727882
DOI: 10.1016/j.jpsychires.2007.07.009 -
Effects of iloperidone, combined with desipramine, on alcohol drinking in the Syrian golden hamster.Neuropharmacology Jun 2016Alcohol use disorder in patients with schizophrenia dramatically worsens their clinical course, and few treatment options are available. Clozapine appears to reduce...
Alcohol use disorder in patients with schizophrenia dramatically worsens their clinical course, and few treatment options are available. Clozapine appears to reduce alcohol use in these patients, but its toxicity limits its use. To create a safer clozapine-like drug, we tested whether the antipsychotic iloperidone, a drug that combines a weak dopamine D2 receptor blockade and a potent norepinephrine alpha-2 receptor blockade would reduce alcohol drinking, and whether its effect on alcohol drinking could be increased if combined with an agent to facilitate norepinephrine activity. Syrian golden hamsters (useful animal model for screening drugs that reduce alcohol drinking in patients with schizophrenia) were given free access to water and alcohol (15% v/v) until stable drinking was established. Animals (n = 6-7/group), matched according to alcohol intake, were treated daily with each drug (iloperidone; clozapine; haloperidol; desipramine [norepinephrine reuptake inhibitor]; with idazoxan [norepinephrine alpha-2 receptor antagonist]) or with a two-drug (iloperidone + desipramine; iloperidone + idazoxan) combination for 14 days. Moderate doses of iloperidone (1-5 mg/kg) significantly reduced alcohol drinking (p < 0.05) in the hamster, whereas higher doses (10-20 mg/kg) did not. In addition, 5 mg/kg of iloperidone reduced alcohol drinking to the same extent as clozapine (8 mg/kg), whereas haloperidol (0.2 mg/kg) did not. Moreover, iloperidone's effects were enhanced via the addition of desipramine (3 mg/kg), but not idazoxan (1.5/3 mg/kg). In this animal model, iloperidone decreases alcohol drinking as effectively as clozapine, and desipramine appears to amplify this effect. The data suggest that iloperidone, alone or in combination with desipramine, should be tested in patients with schizophrenia and alcohol use disorder.
Topics: Adrenergic Uptake Inhibitors; Alcohol Drinking; Animals; Antipsychotic Agents; Clozapine; Cricetinae; Desipramine; Isoxazoles; Male; Mesocricetus; Piperidines
PubMed: 26796639
DOI: 10.1016/j.neuropharm.2016.01.017 -
Zhongguo Yao Li Xue Bao = Acta... Oct 1999To assess the protective effect of desipramine (Des) and fluoxetine (Flu) on the neurons against the lesion induced by a selective serotonergic neurotoxin in vitro.
AIM
To assess the protective effect of desipramine (Des) and fluoxetine (Flu) on the neurons against the lesion induced by a selective serotonergic neurotoxin in vitro.
METHODS
The 10-day cultured primary neurons of hippocampus and cortex of rat was exposed to 5,7-dihydroxytryptamine (5,7-DHT) to determine the optimal lesion concentration and duration. Before exposing to 5,7-DHT, Des and Flu was added to the medium for 30 min to observe the protective effects.
RESULTS
The optimal concentration and duration for 5,7-DHT was 600 micromol.L-1 and 4 h, respectively. Both Des and Flu showed a protective effect in the dose range of 0.8 micromol.L-1 to 10 micromol.L-1 and 0.04 micromol.L-1 to 0.6 micromol.L-1, respectively, when the neurons were injured by 5,7-DHT 600 micromol.L-1 for 4 h. Flu showed a higher efficacy than Des. Both exhibited a more powerful protective effect on the hippocampal neuron than on the cortical neuron.
CONCLUSION
The antidepressant effect of Des and Flu was attributed to their protective effect on the injured serotonergic neuron of the hippocampus and the cortex.
Topics: 5,7-Dihydroxytryptamine; Animals; Animals, Newborn; Antidepressive Agents; Cells, Cultured; Cerebral Cortex; Desipramine; Fluoxetine; Hippocampus; Neurons; Neuroprotective Agents; Rats; Rats, Wistar
PubMed: 11270986
DOI: No ID Found