citalopram Celexa
beta-CIT SPECT demonstrates blockade of 5HT-uptake sites by citalopram in the human brain in vivo.

Pirker W, Asenbaum S, Kasper S, Walter H, Angelberger P, Koch G, Pozzera A, Deecke L, Podreka I, Brucke T.

Neurological University Clinic, Vienna, Austria.

The cocaine analogue 2-beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (beta-CIT) is a potent ligand for both dopamine- and serotonin uptake sites which in its 123I labeled form can be used for single photon emission computerized tomography (SPECT). It was demonstrated previously by SPECT-studies in non-human primates that 123I-beta-CIT binds to dopamine transporters in the striatum and to serotonin transporters in hypothalamus and midbrain. The aim of the present study was to compare 123I-beta-CIT binding in the brain stem of normal controls and a group of subjects under treatment with the selective serotonin reuptake inhibitor (SSRI) citalopram. 123I-beta-CIT-SPECT was performed in 12 depressed patients under 20 mg (n = 5), 40 mg (n = 6) and 60 mg (n = 1) citalopram daily, in one untreated depressed patient and in 11 controls at regular time intervals up till 24 hours p.inj. A highly significant reduction of beta-CIT binding was found in an area including mesial thalamus, hypothalamus, midbrain and pons in patients under citalopram compared to controls (44.1 +/- 14.4 vs. 82.3 +/- 18.6cpm's/mCi x kg body weight; specific binding 4 hrs p.inj.; p = 0.0001). No differences were seen between the high and low dose group and no changes were found in the striatum. 123I-beta-CIT binding in the brain stem and striatum in one untreated depressed patient fell within the range of control values. To our knowledge this is the first report directly demonstrating the effect of a selective serotonin uptake inhibitor in the brain in humans in vivo. SPECT measurements of serotonin uptake sites in patients with depression and other psychiatric disorders might provide better insights into the pathophysiology of these disorders and into mechanisms of drug action.

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citalopram Celexa
Effect of a specific 5-HT uptake inhibitor, citalopram (Lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro.

Hyttel J.

The uptake of 3H-5-HT in synaptosomes from rat brains was investigated. Addition of DA or NA had only a slight or no effect on the uptake. When the uptake into NA and DA neurons was inhibited by the addition of high concentrations of NA and DA, the uptake of 3H-5-HT was unchanged. This was also found after destruction of NA and DA neurons by 6-hydroxydopamine treatment. Furthermore, the uptake of 3H-5-HT was almost equal in different brain parts containing NA and DA in very different amounts. These observations show that the uptake measured with 3H-5-HT is specific for 5-HT neurons. The present study revealed that citalopram and chlorimipramine inhibited uptake competitively, and in this respect the two drugs were equipotent. Compared with a series of tricyclic thymoleptics, the two drugs were the most potent inhibitors of 5-HT uptake, about 20 to 35 times more active than imipramine and amitriptyline. The metabolites of citalopram were also rather potent. The results obtained in the present study correlate closely with those obtained using inhibition of 14C-5-HT uptake in blood platelets, or using the inhibition of H 75/12-induced 5-HT depletion in rat brain. When rats were treated orally with citalopram or chlorimipramine, the inhibition of 3H-5-HT uptake in synaptosomes derived from these rats was two times greater after citalopram than after chlorimipramine.

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citalopram Celexa
Hepatotoxicity of citalopram in rats and first-pass metabolism.

Fredricson Overo K, Svendsen O.

A chronic oral toxicity study of citalopram in rats revealed dose dependent hepatic fatty infiltrations in male rats while female rats were unaffected. Subsequent studies demonstrated markedly reduced availability due to first-pass hepatic metabolism in male rats and roughly complete availability in females. Pretreatment of male rats with phenobarbital for 2 weeks caused increased metabolism and simultaneous administration of phenobarbital and citalopram gave more pronounced fatty infiltrations than citalopram alone. A connection is suggested between the first-pass metabolism in male rats and the hepatotoxicity, which is possibly mediated through a metabolite or intermediate formed in toxic amount during the first passage of the liver.

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citalopram Celexa
Amitriptyline and femoxetine, but not clomipramine or citalopram, antagonize hyperthermia induced by directly acting 5-hydroxytryptamine-like drugs in heat adapted rats.

Pawlowski L.

5-HT uptake inhibitors and pirenperone (a 5-HT2 receptor antagonist), which in previous experiments antagonized fenfluramine (5-HT releaser)-induced hyperthermia in heat adapted rats, were tested against hyperthermia induced by the directly acting 5-HT agonist--m-CPP and quipazine. Pirenperone and --to a lesser degree--amitriptyline and femoxetine antagonized the hyperthermia. Citalopram and clomipramine were inactive. It is concluded that hyperthermia induced by 5-HT-like drugs in rats is due to the stimulation of the 5-HT2 receptor and that the antagonistic effect of citalopram and clomipramine against fenfluramine-induced hyperthermia might be connected with their effect on the uptake of 5-HT.

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citalopram Celexa
Effect of citalopram (Lu 10-171) on tranylcypromine and tryptophan-induced wet-dog shakes in rats.

Keshavan HJ, Gurbani NK, Dandiya PC.

It has been found that citalopram (Lu 10-171) has profound effects on serotonin (5-HT) metabolism by increasing the 5-HT levels in the cerebellum, medulla, and the whole brain with a corresponding decrease of the 5-HIAA levels in all parts of the brain except the brain stem. On the other hand, the drug does not appear to have any influence on the wet-dog shakes response induced by the combination of a monoamine oxidase inhibitor (MAOI) and L-tryptophan. It is suggested that by increasing the neuronal levels of 5-HT, citalopram decreases the turnover of 5-HT and firing rate of serotonin neurons. It has also been observed that citalopram could be an agonist of a certain type of 5-HT receptor which does not respond to the behavioral screening model proposed by Bedard and Pycock (1977).

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citalopram Celexa
Citalopram: a new potent inhibitor of serotonin (5-HT) uptake with central 5-HT-mimetic properties.

Pawlowski L, Ruczynska J, Gorka Z.

Citalopram (1--16 mg/kg), but not amitriptyline, clomipramine, imipramine or zimelidine, stimulated the hind limb flexor reflex in the spinal rat. This stimulatory effect was abolished by serotonin (5-HT) receptor blocking agents (cyproheptadine, metergoline) and prevented ty p-chlorophenylalanine, an inhibitor of 5-HT synthesis. Citalopram (20 mg/kg), similarly but more strongly than clomipramine (20 mg/kg), prevented both fenfluramine- and p-chloroamphetamine-induced hyperthermia in rats kept at 28 degrees C. In contrast to amitriptyline and imipramine, citalopram did not reduce the number of quipazine-induced head twitches in rats (ID50 greater than 50 mg/kg). Also, unlike the above mentioned antidepressants, it did not antagonize, but rather potentiated the 5-HT-mediated rise in blood pressure in pithed rats. The results obtained indicate that, unlike the presently known inhibitors of 5-HT uptake, citalopram considerably potentiates serotonergic transmission, possibly by producing very strong inhibition of uptake without simultaneous blockade of the postsynaptic 5-HT receptors.

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citalopram Celexa
Citalopram-induced generalized lipidosis in rats.

Lullmann-Rauch R, Nassberger L.

This study was focussed on the question of whether or not the potential antidepressant citalopram, which is an amphiphilic cationic compound, can induce generalized lipidosis in animals. In a short term experiment, female rats were treated with a single oral dose (100 mg/kg) and the lymph node was examined by electron microscopy; a significant number of lymphocytes showed lamellated inclusions indicating lipidosis. In a subchronic experiment (7 weeks) female rats received 140 mg/kg per day, and several organs were examined. Marked lipidosis-like alterations were found in lymph node, adrenal cortex and medulla, kidney, lung and in a sympathetic ganglion. Mild lysosomal alterations were found in hepatocytes and retinal pigment epithelium. Lipidosis was very weak, or absent, in retinal ganglion cells, trigeminal ganglion cells and in hypothalamic neurosecretory perikarya. In addition, citalopram produced myopathic alterations in soleus muscle resembling those previously induced with other cationic amphiphilic drugs. Myopathy persisted during a drug-free recovery period of 4 weeks, whereas generalized lipidosis was reversible within 2-4 weeks. The present results support a previously proposed concept concerning the structure-response relationships underlying drug-induced lipidosis.

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citalopram Celexa
Comparative animal studies on cardiovascular toxicity of tri- and tetracyclic antidepressants and citalopram; relation to drug plasma levels.

Boeck V, Jorgensen A, Fredricson Overo K.

The aim of the present study was to compare cardiovascular and/or cardiotoxic effects of eight anti-depressants (imipramine, chlorimipramine, amitriptyline, nortriptyline , doxepin, maprotiline, mianserin and citalopram) in anaesthetized cats after oral dosing and in conscious rabbits after intravenous infusion. In the cats drug plasma levels were determined as well. When estimated from ECG recordings, citalopram and chlorimipramine in particular, but also mianserin, appeared less cardiotoxic than the other drugs tested. The cardiovascular effects seen in the cats were with few exceptions identical for all the drugs tested but not seen at the same dose (concentration). Safety margins were defined as minimal doses or plasma levels when ECG changes (conduction or rhythm) or cardiovascular effects (+/- 10% change of initial value in a series of parameters) occurred in experimental animals divided by maximal therapeutic dose or mean plasma levels in patients. From comparisons of the safety margins it is concluded that except for citalopram and mianserin (safety margins 80 and 18 respectively in cats and greater than 15 in rabbits) all the other drugs tested (safety margins less than or equal to 9) have a cardiotoxic potential. The probability that cardiovascular side effects may occur is less pronounced for citalopram (safety margins 10-32) than for all the other drugs tested (safety margins ranging from 0.1 to less than 5).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6427813&dopt=Abstract citalopram Celexa