Selective serotonin reuptake inhibitors directly signal for apoptosis in biopsy-like Burkitt lymphoma cells.
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Selective serotonin reuptake inhibitors (SSRIs) are the treatment of choice for clinical depression and a range of anxiety-related disorders. They are well tolerated over extended periods with more than 50 million people worldwide benefiting from their use. Here we show that 3 structurally distinct SSRIs--fluoxetine, paroxetine, and citalopram--act directly on Burkitt lymphoma (BL) cells to trigger rapid and extensive programmed cell death. SSRIs unexpectedly stimulated calcium flux, tyrosine phosphorylation, and down-regulation of the c-myc and nm23 genes in Burkitt lymphoma cells remaining faithful to the biopsy phenotype. Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2. Normal peripheral blood mononuclear cells and tonsil B cells, whether resting or stimulated into cycle, were largely resistant to SSRI-induced death as were 5 non-BL lymphoid cell lines tested. We discuss these findings within the context of whether the SSRI class of antidepressants could find future application as potential therapeutics for the highly aggressive and-because of its association with AIDS-increasingly more common Burkitt lymphoma. (+info)
Antidepressant induced cholestasis: hepatocellular redistribution of multidrug resistant protein (MRP2).
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BACKGROUND: We report two cases of antidepressant induced cholestasis. CASE REPORTS: We describe the first reported case of acute cholestasis due to citalopram (selective serotonin reuptake inhibitor) occurring in a patient who also experienced obstetric cholestasis in association with each of three pregnancies; in a second patient cholestasis developed due to dothiepin (tricyclic antidepressant), and six years later due to paroxetine. In both cases liver biopsies showed features of a "pure" cholestasis with total resolution within 1-6 months after withdrawal of the causative drug. Immunostaining for the canalicular transporter, multidrug resistant protein 2 (MRP2), responsible for biliary secretion of several organic anions including bilirubin glucuronides, showed sustained expression in both biopsies as well as relocalisation with appearance of strong staining of the basolateral membrane of the hepatocyte. This finding has also not been reported previously. CONCLUSIONS: We postulate that intracellular redistribution of MRP2 may reflect an adaptive compensatory mechanism which helps in the elimination of the drug or its cholestatic metabolites from the hepatocyte back to the sinusoidal space and subsequent excretion in urine. Changes seen in these two patients differ from findings previously reported in rats where downregulation of mrp2 occurs in response to experimentally induced cholestasis. We speculate that the rat is more advanced than humans in its ability to downregulate canalicular transporter expression as protection against progressive intrahepatic cholestasis. (+info)
5-HT 1A/1B receptor-mediated effects of the selective serotonin reuptake inhibitor, citalopram, on sleep: studies in 5-HT 1A and 5-HT 1B knockout mice.
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Selective serotonin reuptake inhibitors (SSRIs) are extensively used for the treatment of depression. Aside from their antidepressant properties, they provoke a deficit in paradoxical sleep (PS) that is most probably mediated by the transporter blockade-induced increase in serotonin concentration in the extracellular space. Such an effect can be accounted for by the action of serotonin at various types of serotonergic receptors involved in PS regulation, among which the 5-HT(1A) and 5-HT(1B) types are the best candidates. According to this hypothesis, we examined the effects of citalopram, the most selective SSRI available to date, on sleep in the mouse after inactivation of 5-HT(1A) or 5-HT(1B) receptors, either by homologous recombination of their encoding genes, or pharmacological blockade with selective antagonists. For this purpose, sleep parameters of knockout mice that do not express these receptors and their wild-type counterparts were monitored during 8 h after injection of citalopram alone or in association with 5-HT(1A) or 5-HT(1B) receptor antagonists. Citalopram induced mainly a dose-dependent inhibition of PS during 2-6 h after injection, which was observed in wild-type and 5-HT(1B)-/- mice, but not in 5-HT(1A)-/- mutants. This PS inhibition was fully antagonized by pretreatment with the 5-HT(1A) antagonist WAY 100635, but only partially with the 5-HT(1B) antagonist GR 127935. These data indicate that the action of the SSRI citalopram on sleep in the mouse is essentially mediated by 5-HT(1A) receptors. Such a mechanism of action provides further support to the clinical strategy of antidepressant augmentation by 5-HT(1A) antagonists, because the latter would also counteract the direct sleep-inhibitory side-effects of SSRIs. (+info)
Serotonin syndrome after concomitant treatment with linezolid and citalopram.
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Linezolid, a new synthetic antimicrobial, is an important weapon against methicillin-resistant Staphylococcus aureus (MRSA). Although there are reports of serotonin syndrome developing after concomitant use of linezolid and the selective serotonin reuptake inhibitor paroxitene, this report concerns a patient receiving citalopram who developed thrombocytopenia, serotonin syndrome, and lactic acidosis and died following long-term linezolid therapy. (+info)
Electrocardiographic dose-dependent changes in prophylactic doses of dosulepine, lithium and citalopram.
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Tricyclic antidepressant drugs dosulepine (TCA), serotonin selective reuptake inhibitor (SSRI) and prophylactic agent with antidepressant effect lithium carbonicum (Li) have different cardiovascular side-effects. We compared them in the prophylactic therapy of periodic affective disorder in remission with TCA, SSRI and Li. Our previous papers confirmed the most prominent effects of heart electric field parameters in TCA patients (Slavicek et al., 1998). In the present work we studied for the first time the dose-dependent changes of ECG, body surface potential maps (BSPM - parameter DIAM 30, 40) in 43 TCA dosulepine, 40 SSRI citalopram and 30 Li outpatients (Hamilton scale: HAMDL10; age 40+/-5 years; treated for depressive disorders or bipolar disorders). The daily doses of dosulepine were 50-250 mg, citalopram 20-80 mg, Li plasma levels 0.66+/-0.08 meq/l. The electrocardiogram (ECG), vectorcardiogram (VCG), and BSPM were measured and calculated by the Cardiag 112.1 diagnostic system. The results have shown a relation between the dose of dosulepine and extremum (maximum and minimum) of depolarization isoarea map in dosulepine, but not in citalopram patients. The repolarization BSPM changes were most pronounced in SSRI patients. Lithium in long-term prophylaxy (1-22 years) caused only minimal ECG BSPM changes. The present results correspond with our previous observations. (+info)
The anticonvulsant effect of citalopram as an indirect evidence of serotonergic impairment in human epileptogenesis.
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Some evidence would indicate that a serotonergic deficit may be involved in epileptogenesis. A preliminary trial of citalopram, a selective inhibitor of serotonin reuptake, was carried out. Citalopram 20mg/day was given to 11 non-depressed patients with poorly controlled epilepsy as an add on treatment with an open label design for 8-10 months. The median seizure frequency dropped by 55.6% in the whole group, with nine patients improving by at least 50%. No adverse reactions occurred with the exception of mild drowsiness. There were no changes of post-treatment as compared to pre-treatment AED serum concentrations. Although controlled studies are required to confirm the anticonvulsant effect of citalopram, these findings may be regarded as an indirect evidence of serotonergic impairment in human epileptogenesis. (+info)
Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram.
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1. Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect. 2. In the tail-suspension test (C57/Bl male mice), nicotine (0.8-1.2 mg kg(-1) s.c. or i.p.) given 15-60 min before the measurement exerted no effect on immobility. 3. Given 30 min before the measurement, citalopram (2 mg kg(-1)) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg(-1), 15 but not 40 min before the test) to citalopram-treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg(-1)) did not affect immobility, but given in combination with 0.8 mg kg(-1) of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg(-1)) also produced an enhancement in the anti-immobility effect of imipramine (20 mg kg(-1)). 4. We further investigated if nAChR antagonists would influence the antidepressant-like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1-2.5 mg kg(-1)) and dihydro-beta-erythroidine (2 mg kg(-1)) potentiated the antidepressant-like effect of imipramine (4-20 mg kg(-1)). Mecamylamine (2.5 mg kg(-1)) but not dihydro-beta-erythroidine also increased the antidepressant-like effect produced by 2 mg kg(-1) of citalopram. 5. The interaction between nAChR antagonists and antidepressants appeared synergistic. 6. Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity. 7. The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail-suspension test. (+info)
Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters.
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The selective serotonin reuptake inhibitors (SSRIs) and cocaine bind to the neural serotonin (5-HT) transporter (SERT) and thus inhibit presynaptic reuptake of 5-HT and elevate its concentration in the synaptic cleft. Cocaine also binds to the dopamine transporter (DAT) and to the noradrenaline transporter (NET) and inhibits presynaptic reuptake of dopamine and noradrenaline. SERT, DAT, and NET belong to the sodium/neurotransmitter symporter family, which is predicted to have a molecular structure with 12 transmembrane alpha-helices (TMHs) and intracellular amino- and carboxy terminals. We used an electron density projection map of the Escherichia coli Na+/H+ anti-porter, and site-directed mutagenesis data on DAT and SERT to construct 3-dimensional molecular models of SERT, DAT and NET. These models were used to simulate the molecular interaction mechanisms of the SSRI, S-citalopram, its less potent enantiomer, R-citalopram and of cocaine with the transporters. In the SERT model, a single amino acid (Tyr95) in TMH1 determined the transporter selectivity of S-citalopram for SERT over DAT and NET. A dipole-dipole interaction was formed between the hydroxy group of Tyr95 in SERT and the nitril group of S-citalopram, but could not be formed by S-citalopram in DAT and NET where the corresponding amino acid is a phenylalanine. The lower binding affinity of R-citalopram may be due to sterical hindrance at the binding site. The tropane ring of cocaine interacted with Tyr95 in SERT and with the corresponding phenylalanines in NET and DAT. This may explain why cocaine, but not S-citalopram, has high binding affinity to all three transporters. (+info)