Negative immunoregulatory effects of antidepressants: inhibition of interferon-gamma and stimulation of interleukin-10 secretion.
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There is now some evidence that major depression is accompanied by activation of the inflammatory response system. There is also some evidence that antidepressants may suppress the release of cytokines, such as interleukin-1 beta (IL-1 beta) and IL-6 by activated monocytes and IL-2 and interferon-gamma (IFN gamma) by activated T cells. This study was carried out to examine the effects of clomipramine, sertraline, and trazodone on the stimulated production of IFN gamma, a pro-inflammatory cytokine, and IL-10, a negative immunoregulatory cytokine. Whole blood of nine healthy volunteers was stimulated with PHA, 5 micrograms/mL and LPS, 25 micrograms/mL for 72 hr with and without incubation with clomipramine, 10(-6) and 10(-9) M, sertraline, 10(-6) and 10(-8) M, and trazodone, 10(-6) and 10(-8) M. All three antidepressants significantly reduced IFN gamma secretion, whereas clomipramine and sertraline significantly increased IL-10 secretion in culture supernatant. All three antidepressants significantly reduced the IFN gamma/IL-10 ratio. The results suggest that antidepressants, at concentrations in the therapeutical range, have negative immunoregulatory effects through inhibition of IFN gamma and stimulation of IL-10 release. (+info)
Clomipramine-induced urinary retention in a cat.
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A 10-year-old, female, spayed shorthair with presumed psychogenic alopecia was treated with clomipramine (1 mg/kg body weight/day). The cat developed urinary retention within 2 days. Clomipramine was discontinued. Clinical signs resolved over the next 7 days. The urinary retention was attributed to the anticholinergic effects of clomipramine. (+info)
Clomipramine N-demethylation metabolism in human liver microsomes.
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AIM: To study the effect of cytochrome P-450 (CYP450) inhibitors on clomipramine (Clo) N-demethylation in vitro. METHODS: The kinetic parameters of Clo N-demethylation in human liver microsomes were obtained by the Michaelis-Menten equation. The parameters after pretreatment with putative inhibitors of various CYP450 isoforms were compared with controls. RESULTS: K(m1), K(m2), Vmax1, Vmax2, Vmax1/K(m1), and Vmax2/K(m2) were (0.11 +/- 0.06), (24 +/- 14) mumol.L-1, (114 +/- 47), (428 +/- 188) nmol.g-1.min-1, (1.8 +/- 1.6), and (0.019 +/- 0.005) L.g-1.min-1, respectively. The interindividual variations for the last 4 parameters reached up to 2.5-, 7.3-, 3.4-, and 1.8-fold. At 5 mumol.L-1 of Clo, troleandomycin (Tro), furafylline (Fur), ditiocarb sodium (Dit), and S-mephenytoin (Mep) produced a marked inhibition on Clo N-demethylation while sulfaphenazole (Sul) and quinidine (Qui) had only slight effects. The inhibitory rates by Dit 30, Mep 500, Fur 10, Tro 10, Fur 80, Tro 200 and Fur 80 + Tro 200 mumol.L-1 were 27.0%, 32.9%, 42.8%, 40.5%, 63.9%, 66.4%, and 78.3%, respectively. The IC50 (95% confidence limits) for Fur and Tro were 27.7 (19.1-36.3) and 42.1 (20.9-63.3) mumol.L-1, respectively. CONCLUSIONS: The N-demethylation of Clo exhibited a biphasic behavior. This reaction was mediated mainly by both CYP1A2 and CYP3A4, to a minor extent by CYP2C19 at the low concentration of Clo in vitro. (+info)
Local treatments of dorsal raphe nucleus induce changes in serotonergic activity in rat major cerebral arteries.
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BACKGROUND AND PURPOSE: Rat major cerebral arteries seem to receive serotonergic fibers originating from the dorsal raphe nucleus (DRN), but little is known about their function. The aim of our present work was to establish a functional relationship between this brain stem nucleus and the cerebral blood vessels by studying the effects of several treatments in the DRN on cerebrovascular serotonergic activity. METHODS: Serotonin, clomipramine, 8-OH-DPAT, and WAY-100635 were administered in DRN. A stereotaxically localized electrode allowed the electrical stimulation of this brain stem nucleus. Serotonergic activity was appraised in major cerebral arteries, striatum, and hippocampus from 5-hydroxytryptophan accumulation after aromatic L-amino acid decarboxylase inhibition with NSD-1015. RESULTS: Serotonin significantly decreased serotonergic activity in major cerebral arteries and striatum without affecting it in hippocampus. This reduction was blocked by previous injection of WAY-100635 in DRN. Local administration of 8-OH-DPAT or clomipramine elicited an effect similar to that of serotonin, whereas that of WAY-100635 did not modify serotonergic activity in either of the tissues. Electrical stimulation of DRN significantly increased serotonergic activity in major cerebral arteries and striatum but not in hippocampus. CONCLUSIONS: These results confirm the presence of a serotonergic innervation in rat major cerebral arteries functionally related to DRN. 5-HT(1A) receptor activation partly mediates the action of serotonin in DRN. A serotonergic tone acting on these somatodendritic receptors was not clearly found. (+info)
Recovery of dopamine neuronal transporter but lack of change of its mRNA in substantia nigra after inactivation by a new irreversible inhibitor characterized in vitro and ex vivo in the rat.
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1. In vitro, the ability of DEEP-NCS {1-[2-(diphenylmethoxy)ethyl]-4-[2-(4-isothiocyanatophenyl)ethyl]- piperazine} to inhibit [3H]-dopamine uptake by rat striatal synaptosomes was concentration-dependent and inversely related to the protein concentration. This inhibition was irreversible and resulted from changes in Vmax and KM. DEEP-NCS was less potent on noradrenaline, serotonin and choline transport. 2. One day after intrastriatal injections of DEEP-NCS (100 and 1000 pmol) in 20% dimethylsulphoxide, moderate decreases in the ex vivo dopamine uptake were observed in synaptosomes obtained from striatum injected with DEEP-NCS or solvent, and the contralateral uninjected striatum. 3. In similar conditions, 300 pmol DEEP-NCS in 45% 2 hydroxypropyl-gamma-cyclodextrin - 0.5% dimethylsulphoxide solution sub-totally reduced ex vivo dopamine uptake and mazindol binding, and moderately decreased choline and serotonin transport. These reductions were specific to DEEP-NCS-injected striata. A clomipramine pretreatment (16 mg kg-1 i.p. 1 h before) was performed in following experiments, since it reduced the DEEP-NCS-elicited decrease in serotonin uptake without affecting other indices. 4. One day after intrastriatal injection, DEEP-NCS elicited similar dose-dependent decreases in ex vivo dopamine uptake and mazindol binding (ID50=6.9-8 ng striatum-1). Changes in KM and Vmax for ex vivo dopamine transport produced by DEEP-NCS disappeared according to similar time-courses. 5. The t(1/2) for transporter recovery was 6. 1 days. This value should correspond to its actual turnover rate in vivo, since no change in transporter mRNA level was observed in substantia nigra ipsilateral to 300 pmol DEEP-NCS-injected striatum. 6. The results indicate that DEEP-NCS behaves as a potent, quite selective, irreversible inhibitor of the DAT, in vitro and in vivo. Its use in vivo suggests that the physiological half-life of the rat striatal DAT is close to 6 days. (+info)
Citalopram controls phobic symptoms in patients with panic disorder: randomized controlled trial.
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OBJECTIVE: To examine the effects of long-term treatment with citalopram or clomipramine on subjective phobic symptoms in patients with panic disorder. DESIGN: Double-blind, parallel-group, five-arm study. PATIENTS: Patients aged 18 to 65 years with panic disorder (DMS-III-R diagnosis) and with no major depressive symptoms. INTERVENTIONS: Four hundred and seventy-five patients were randomized to 8 weeks of treatment with either citalopram (10 to 15 mg per day; 20 to 30 mg per day; or 40 to 60 mg per day), clomipramine (60 to 90 mg per day) or placebo. Two hundred and seventy-nine patients continued treatment after the 8-week acute phase. OUTCOME MEASURES: Phobic symptoms were assessed using the Phobia Scale and the Symptom Checklist's (SCL-90) phobia-related factors. RESULTS: At all dosages, citalopram was more efficacious than placebo, with 20 to 30 mg generally being the most effective dosage. Citalopram (20 to 30 mg) generally decreased phobic symptoms significantly more than placebo after Month 3. Interpersonal sensitivity decreased when measured on the respective SCL-90 sub-scale. Alleviation of phobic symptoms generally continued to increase towards the end of the treatment. The effect of clomipramine was not as consistent. CONCLUSIONS: All active treatment groups, especially the group receiving 20 to 30 mg per day of citalopram, effectively controlled phobic symptoms in patients with panic disorder. Long-term treatment with citalopram further decreased phobic symptoms. (+info)
Effect of clomipramine on monoamine metabolites in the cerebrospinal fluid of behaviorally normal dogs.
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The tricyclic antidepressant, clomipramine, is an effective treatment for canine compulsive disorder (canine CD). This disorder is a clinical syndrome of abnormal conflict behaviors and its pathophysiology is unknown. However, because clomipramine is an effective treatment, information about the drug's neurochemical effect could enhance the understanding of canine CD. The following experiment used 6 behaviorally normal dogs to assess the effect of clomipramine (3 mg/kg, q24h, PO) on the central turnover of 3 monoamines (serotonin, dopamine, and norepinephrine) as measured by the concentrations of their respective metabolites in cerebrospinal fluid (CSF). In a randomized, placebo-controlled, AB-BA crossover experiment, cisternal CSF was taken after 1, 2, 4, and 6 wk on each treatment. No effect of clomipramine was detected. This contrasts with human studies that have suggested that clomipramine affects the concentrations of monoamine metabolites in lumbar CSF. However, those papers do not address methodological assumptions, such as (i) metabolites in CSF originate only from the brain, and (ii) concentrations of metabolites in cisternal/lumbar CSF reflect the concentrations in local areas of the brain. Notwithstanding the small sample size, our results suggest that more localized sampling techniques (e.g. microdialysis) are needed when examining the effect of drugs on central monoamine metabolites. Clomipramine's efficacy for canine CD indicates the need for neurobiological research and, to our knowledge, our study is the first of its kind in dogs. The resulting data are preliminary but they can inform optimal neurobiological studies of canine CD. (+info)
Determination of fluoxetine, fluvoxamine, and clomipramine in pharmaceutical formulations by capillary gas chromatography.
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A simple and fast capillary gas chromatographic method with flame ionization detection is proposed for the simultaneous determination of fluoxetine, fluvoxamine, and clomipramine without a prederivatization. The reported method is the first one that allows the determination of three selective serotonin reuptake inhibitors. Optimal conditions for the quantitative separation were investigated: column head pressure (80 kPa), injector and detector temperatures (260 and 250 degrees C), time and temperature for the splitless step (0.75 min and 60 degrees C), size of sample (2 microL), and oven temperature program, providing analysis times shorter than 10 min. Aspects such as the stability of the solutions, linearity, accuracy, and precision are examined in order to validate this method. Peak purity and detection and quantitation limits are also assessed using mass selective detection. The scope of the validated method is tested in the analysis of pharmaceutical preparations, with recoveries between 97.5 and 102.5% with regard to their nominal contents. (+info)