citalopram Celexa
[11C]-NS 4194 versus [11C]-DASB for PET imaging of serotonin transporters in living porcine brain.

Jensen SB, Smith DF, Bender D, Jakobsen S, Peters D, Nielsen EO, Olsen GM, Scheel-Kruger J, Wilson A, Cumming P.

PET Center, Aarhus University Hospitals, Aarhus, Denmark.

In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12774301&dopt=Abstract citalopram Celexa



citalopram Celexa
The involvement of dopamine (DA) and serotonin (5-HT) in stress-induced stereotypies in bank voles (Clethrionomys glareolus).

Schoenecker B, Heller KE.

Zoological Institute, University of Copenhagen, Tagensvej 16, DK-2200 N, Copenhagen, Denmark

In order to clarify the dependency of stress-induced stereotypies on dopamine (DA) and serotonin (5-HT) functioning, undisturbed and acutely stressed stereotyping bank voles were treated during 3 weeks with the commonly used human atypical neurolepticum clozapine and the SSRI antidepressant citalopram. Clozapine blocks DA receptors (D sub (4)) and acts as a partial 5-HT antagonist (5-HT sub (2) receptors), while citalopram increases 5-HT transmitter activity. Levels of stereotypies were quantified under undisturbed conditions during the treatment period and immediately after the acute stress of handling and injections. It was demonstrated that stereotypies are markedly increased after acute stress and that citalopram effectively mitigates this stress effect. Stereotypies under undisturbed conditions were left unaffected by both clozapine and citalopram treatments.It is suggested that stress-induced increases in stereotypies are more dependent on 5-HT than DA functioning.

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citalopram Celexa
Distribution of serotonin, its metabolites and 5-HT transporters in the neostriatum of Lurcher and weaver mutant mice.

Reader TA, Hebert C, Ase AR, Le Marec N.

Centre de Recherche en Sciences Neurologiques, Departement de Physiologie, Faculte de Medecine, Universite de Montreal, CP6128 Succursale Centre-Ville, Montreal, Quebec, Canada H3C 3J7. tomas.a.reader umontreal.ca

Serotonin (5-HT) uptake sites, or transporters, were measured in the neostriatum (caudate putamen) of wild type (+/+) mice and heterozygous (wv/+) and homozygous (wv/wv) weaver, as well as in heterozygous Lurcher (Lc/+) mutants. These topological surveys were carried out by quantitative ligand binding autoradiography using the uptake site antagonist [3H]-citalopram as a probe of innervation densities in four quadrants of the rostral neostriatum and in two halves of the caudal neostriatum. In addition, tissue concentrations of 5-HT, 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol were measured by high-performance liquid chromatography with electrochemical detection in these neostriatal divisions. In +/+ mice and in Lc/+ mutants there was a dorso-ventral gradient of increasing 5-HT levels, and they exhibited a similar heterogeneity of [3H]-citalopram labeling. In contrast, the gradients of 5-HT concentrations and [3H]-citalopram binding disappeared in the weaver mutants, suggesting a rearrangement of the 5-HT innervation. This reorganization of the 5-HT system in the neostriatum was more obvious in the wv/wv and is compatible with the hypothesis that the postnatal dopaminergic deficiencies that characterize weaver mutants lead to a sprouting of fibers and thus constitute a genetic model of dopaminergic denervation that leads to a 5-HT hyperinnervation.

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citalopram Celexa
A retrospective study of citalopram in adolescents with depression.

Bostic JQ, Prince J, Brown K, Place S.

Department of Child Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston 02114-3139, USA.

Recent evidence suggests that the selective serotonin reuptake inhibitors are safe and efficacious in treating juveniles with depression. However, citalopram has not been reported in adolescents with depression. This study assessed the effectiveness and tolerability of citalopram in all adolescents with depressive disorders treated naturalistically in a community mental health center during a 1-year interval. Medical charts were retrospectively reviewed for 21 adolescents treated with citalopram for major depression (n = 14), bipolar depression (n = 4), or dysthymia (n = 3). An independent rater compared last visit to baseline depression using the Clinical Global Impression (CGI) Severity and Improvement scales. Adolescents received citalopram for an average of 128.5 +/- 84 days at a final average dose of 26.5 +/- 13.1 mg/day. Sixteen of these 21 adolescents (76%) exhibited much to very much improvement as measured by the CGI, and severity of depression diminished significantly (z = 3.007, p < 0.0026). Mild side effects, including headaches, dizziness, nausea, sedation, agitation, and sweating were reported by 7 (33%) of the patients. These data suggest that citalopram may be effective, safe, and well tolerated in the treatment of adolescents with depressive disorders and that controlled trials are warranted in this population.

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citalopram Celexa
Behavioral and neurochemical effects of anpirtoline and citalopram in isolated and group housed mice.

Rilke O, Will K, Jahkel M, Oehler J.

AG Neurobiologie, Klinik und Poliklinik fur Psychiatrie und Psychotherapie, TU Dresden, Germany. olaf.rilke mailbox.tu-dresden.de

Acute effects of serotonergic drugs acting via different mechanisms were investigated by a social interaction test and subsequent determination of serotonin and dopamine metabolisms in mice housed in groups or isolated for 6 weeks. A resident/intruder test was performed with anpirtoline (5-HT1B receptor agonist in rodents; 1 mg/kg), citalopram (SSRI; 0.5 mg/kg) and saline treatment before animals were decapitated and different brain regions were frozen for subsequent HPLC-analyses. Behavioral investigations indicated a strong increase of aggressive behavior after 6 weeks of isolation housing. Acute citalopram treatment did not influence behavioral parameters of isolated and group housed mice. In contrast, anpirtoline antagonized isolation induced aggressive behavioral components in a specific manner. Analysis of dopamine and serotonin metabolism revealed that citalopram treatment did not affect dopamine metabolism, but reduced serotonin metabolism in the striatum, hippocampus, cortex and midbrain independent of housing conditions. In contrast, anpirtoline treatment increased dopamine metabolism in cortex, striatum and midbrain as well as influenced serotonin metabolism in a structure- and state-specific manner. Whereas anpirtoline decreased serotonin metabolism in the cortex, the midbrain and the hippocampus independent of housing conditions, in the striatum anpirtoline abolished the isolation induced decrease of serotonin metabolism. These results indicate that anpirtoline might induce antiaggressive effects via postsynaptic receptor- and structure-specific activation of serotonergic but also dopaminergic processes, whereas structure independent increase of synaptic serotonin via citalopram was ineffective to reverse aggressivity in isolated mice.

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citalopram Celexa
Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram.

von Moltke LL, Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI.

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111, USA. lisa.vonmoltke tufts.edu

Transformation of escitalopram (S-CT), the pharmacologically active S-enantiometer of citalopram, to S-desmethyl-CT (S-DCT), and of S-DCT to S-didesmethyl-CT (S-DDCT), was studied in human liver microsomes and in expressed cytochromes (CYPs). Biotransformation of the R-enantiomer (R-CT) was studied in parallel. S-CT was transformed to S-DCT by CYP2C19 (K(m) = 69 microM), CYP2D6 (K(m) = 29 microM), and CYP3A4 (K(m) = 588 microM). After normalization for hepatic abundance, relative contributions to net intrinsic clearance were 37% for CYP2C19, 28% for CYP2D6, and 35% for CYP3A4. At 10 microM S-CT in liver microsomes, S-DCT formation was reduced to 60% of control by 1 microM ketoconazole, and to 80 to 85% of control by 5 microM quinidine or 25 microM omeprazole. S-DDCT was formed from S-DCT only by CYP2D6; incomplete inhibition by quinidine in liver microsomes indicated participation of a non-CYP pathway. Based on established index reactions, S-CT and S-DCT were negligible inhibitors (IC(50) > 100 microM) of CYP1A2, -2C9, -2C19, -2E1, and -3A, and weakly inhibited CYP2D6 (IC(50) = 70-80 microM). R-CT and its metabolites, studied using the same procedures, had properties very similar to those of the corresponding S-enantiomers. Thus S-CT, biotransformed by three CYP isoforms in parallel, is unlikely to be affected by drug interactions or genetic polymorphisms. S-CT and S-DCT are also unlikely to cause clinically important drug interactions via CYP inhibition.

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citalopram Celexa
S33005, a novel ligand at both serotonin and norepinephrine transporters: II. Behavioral profile in comparison with venlafaxine, reboxetine, citalopram, and clomipramine.

Millan MJ, Dekeyne A, Papp M, La Rochelle CD, MacSweeny C, Peglion JL, Brocco M.

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France. mark.millan fr.netgrs.com

Reflecting its potent inhibition of serotonin (5-HT) reuptake (accompanying paper), S33005 blocked spontaneous tail-flicks induced by parachloroamphetamine in rats. This action was mimicked by the 5-HT reuptake inhibitor, citalopram, and the 5-HT/norepinephrine (NE) reuptake inhibitor, venlafaxine, whereas the preferential NE reuptake inhibitor, reboxetine, was inactive. Consistent with its less potent interaction with NE transporters, higher doses of S33005 attenuated induction of hypothermia by reserpine, an action mimicked by reboxetine and venlafaxine, whereas citalopram was ineffective. In mice, S33005 reduced immobility in forced-swim and tail-suspension procedures. It also inhibited marble-burying behavior and suppressed aggressive behavior between resident and intruder animals. In rats, S33005 generalized to a discriminative stimulus elicited by citalopram and attenuated hypnotic-sedative actions of the alpha2-adrenoceptor agonist, S18616. For these parameters, S33005 was a more potent agent (median, 1.2 mg/kg, s.c.) than venlafaxine, citalopram, reboxetine, or the tricyclic agent, clomipramine. Even at markedly higher doses (40.0-80.0 mg/kg, s.c.), S33005 little affected motor behavior. S33005 (10.0 mg/kg, s.c.) also increased responses in a learned helplessness paradigm in rats, whereas venlafaxine was ineffective. Finally, in a rat chronic mild-stress model, S33005 dose- (2.5-40.0 mg/kg) and time- (2-5 weeks) dependently enhanced sucrose consumption. Venlafaxine was likewise active in this procedure. In conclusion, in line with its inhibition of 5-HT and (less potently) NE reuptake, S33005 is active in a broad range of models suggestive of antidepressant activity. It exerts its actions more potently than venlafaxine and clomipramine, and its overall profile is distinct from those of citalopram and reboxetine.

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citalopram Celexa
Citalopram in refractory obsessive-compulsive disorder: an open study.

Marazziti D, Dell'Osso L, Gemignani A, Ciapparelli A, Presta S, Nasso ED, Pfanner C, Cassano GB.

Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Italy. dmarazzi psico.med.unipi.it

This study aimed to evaluate the effect of citalopram in patients with refractory obsessive-compulsive disorder (OCD) which had not responded to previous antiobsessional treatments. Eighteen patients were selected for this study: they had been suffering from OCD, according to DSM-IV criteria, for at least 2 years and had various comorbid disorders. All had been treated with serotonin reuptake inhibitors at adequate dosages for at least 6 months, but had failed to respond. Consequently, they were shifted to citalopram, titrated up to the dose of 40 mg, within 2 weeks. After 4 months of this regimen, 14 out of the total of 18 patients had shown a reduction in OC symptoms, as assessed by the decrease in the Yale-Brown Obsessive Compulsive Scale total score; no relevant side-effects were reported, except for a mild nausea in four patients within the first few days of treatment, which quickly disappeared. The use of citalopram would appear to be an useful strategy in refractory OCD cases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11459335&dopt=Abstract citalopram Celexa