citalopram Celexa
Potentiation of DOM-induced stimulus control by fluoxetine and citalopram: role of pharmacokinetics.

Eckler JR, Doat MM, Rabin RA, Winter JC.

Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, 102 Farber Hall, Buffalo, NY 14214-3000, USA. eckler buffalo.edu

The present investigation examined the interaction between 2,5-dimethoxy-4-methylamphetamine [DOM] and the selective serotonin reuptake inhibitor [SSRI] citalopram in rats trained with DOM [0.6 mg/kg; 75 min pretreatment time] as a discriminative stimulus. Pretreatment with citalopram at a dose of 1.0 mg/kg shifted the DOM dose response relationship to the left. Unlike previously tested SSRI's, the enhancement of DOM-induced stimulus control occurred in the absence of significant partial substitution by citalopram. DOM brain levels were measured using a GC-MS method both in the presence and absence of citalopram and fluoxetine in order to evaluate the pharmacokinetic contribution to the observed behavioral effect. The data indicated that fluoxetine but not citalopram significantly increased DOM brain levels. It is concluded that the effects of DOM as a discriminative stimulus are potentiated by the acute administration of citalopram and this effect is not mediated by additivity or pharmacokinetic mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12106599&dopt=Abstract citalopram Celexa



citalopram Celexa
Impaired spatial learning in the Morris water maze induced by serotonin reuptake inhibitors in rats.

Majlessi N, Naghdi N.

Department of Physiology and Pharmacology, Pasteur Institute of Iran, Pasteur Ave., Tehran 13164, Iran. nahidm institute.pasteur.ac.ir

The effects of selective serotonin reuptake inhibitors citalopram and fluoxetine on spatial learning were assessed in rats. Adult male rats were subjected to 4 days of training in the Morris water maze with the invisible platform. Animals received different doses of citalopram (1-8 mg/kg; i.p.) or fluoxetine (1-16 mg/kg; i.p.) or their vehicles (saline or distilled water respectively) 30 minutes before training each day. The results showed that citalopram at doses of 4 and 8 mg/kg and fluoxetine at doses of 8 and 16 mg/kg significantly increased latencies to find the platform and traveled distances compared to the control group. Therefore, it appears that selective serotonin reuptake inhibitors can cause learning deficits in complex spatial tasks such as Morris water maze. Copyright 2002 Lippincott Williams & Wilkins.

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citalopram Celexa
Effect of citalopram treatment on relationship between platelet serotonin functions and the Karolinska scales of personality in panic patients.

Neuger J, Wistedt B, Aberg-Wistedt A, Stain-Malmgren R.

Karolinska Institute, Institution of Clinical Neuroscience, Department of Psychiatry, St. Goran's Hospital, Stockholm, Sweden. Jolanta.Neuger spo.sll.se

Using the Karolinska Scales of Personality (KSP), we investigated the effect of the selective serotonin reuptake inhibitor citalopram on personality traits and the relationship between personality traits and peripheral indexes for central serotonergic function in patients with panic disorder at baseline and after 6 months of treatment. The degree of anxiety and depression was assessed using the Beck Anxiety Inventory, the Beck Depression Inventory, the Clinical Anxiety Scale, and the Montgomery Asberg Depression Rating Scale. A reduction in anxiety and depression scores of 75% was observed after treatment in two thirds of the patients. Mean changes of 12% in the direction of normalization were observed in all KSP anxiety-related items (Somatic Anxiety, Muscular Tension, Psychic Anxiety, and Psychasthenia), the aggression and hostility related items (Inhibition of Aggression, Irritability, and Guilt) and the item of Socialisation. A positive correlation was found between Vmax for the platelet [14C]-serotonin uptake and Inhibition of Aggression before treatment, and a negative correlation was found between the affinity of serotonin uptake and Inhibition of Aggression after treatment. Negative childhood experiences influenced enhanced scores on some KSP items but not the serotonergic function. In panic patients treated with citalopram, effects were seen on personality traits, confirming an association between serotonergic activity and aggression.

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citalopram Celexa
Predosing with the unlabeled "inactive" enantiomer as a tool for improvement of the PET signal.

Elfving B, Bjornholm B, Knudsen GM.

Neurobiology Research Unit N9201, University Hospital Rigshospitalet, DK-2500 Copenhagen, Denmark. belfving pet.rh.dk

In this study we investigated whether the PET signal of labeled (S)-citalopram could be improved by predosing with the unlabeled distomer (R)-citalopram. Ten minutes before intravenous injection of 1.5 MBq [(3)H]-(S)-citalopram, rats were given i.v. 0.9% saline, 16 or 24 microg (R)-citalopram. Sixty minutes after injection of [(3)H]-(S)-citalopram, the brains were dissected into eight regions. The binding obtained in each brain region was compared to cerebellum as a reference region. Predosing with saline, 16 and 24 microg (R)-citalopram yielded thalamus/cerebellum ratios of 1.6 +/- 0.12, 1.6 +/- 0.12, and 1.1 +/- 0.26 (means +/- SD), respectively. It is concluded that the nonspecific binding of radiolabeled (S)-citalopram cannot be reduced by predosing with the 150 times less active enantiomer (R)-citalopram, possibly due to the pool of nonspecific sites being too large for blocking. Copyright 2002 Wiley-Liss, Inc.

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citalopram Celexa
Stereoselective single-dose kinetics of citalopram and its metabolites in rats.

Kugelberg FC, Carlsson B, Ahlner J, Bengtsson F.

Division of Clinical Pharmacology, Department of Medicine and Care, Faculty of Health Sciences, Linkoping University, Linkoping, Sweden. frederik.kugelberg imv.liu.se

The single-dose kinetics of the enantiomers of citalopram (CIT) and its metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT), were investigated after administration of 10, 20, or 100 mg/kg (s.c.) rac-CIT to rats. Samples from serum and two brain regions were collected 1, 3, 10, or 20 h postdose for HPLC analysis. In the 100 mg/kg rats, the enantiomeric (S/R) serum concentration ratios of CIT decreased during the study period (0.93 at 1 h vs. 0.59 at 20 h; P < 0.001). In the 10 and 20 mg/kg rats, the decrease in serum S/R CIT ratios was not so evident as in the 100 mg/kg rats. In all three groups the S/R CIT ratio was almost the same in the brain as in serum, although both CIT enantiomer levels in the brain were found to be 5-10 times higher than the levels in serum. The serum and brain metabolite levels were low in the 10 and 20 mg/kg rats, whereas the levels increased during the study period in the 100 mg/kg rats. In conclusion, the CIT enantiomers were shown for the first time to be stereoselectively metabolized after single-dose administration to rats, as previously shown in steady-state dosing studies in humans and rats. Copyright 2003 Wiley-Liss, Inc.

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citalopram Celexa
[Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine]

[Article in French]

Owens JM, Knight DL, Nemeroff CB.

University school of Medicine. Dept of Psychiatry and Behavorial sciences, 1639 Pierce drive, suite 4000 WMRB, Atlanta GA 30322, USA.

BACKGROUND: Single isomers of the selective serotonin reuptake inhibitors citalopram (escitalopram, S-citalopram) and fluoxetine (R-fluoxetine) are currently under development for the treatment of depression and other psychiatric disorders. Previous studies conducted in laboratory animals have revealed that the biological effects on serotonin reuptake for citalopram reside in the S enantiomer. In contrast, both enantiomers of fluoxetine contribute to its biological activity. METHODS: In the present study, the potency and selectivity of escitalopram, R-fluoxetine, and all of the other currently available selective serotonine reuptake ihibitors were compared for binding affinity at the human serotonin, norepinephrine, and dopamine transporters and several select neurotransmitter receptors using radioligand binding assays. RESULTS: Both escitalopram and R-fluoxetine were potent inhibitors of the serotonin transporter (Ki=1,1 and 1,4 nmol/L, respectively). escitalopram was the most serotonin transporter-selective compound tested and was approximately 30 fold more potent than R-citalopram. CONCLUSIONS: As noted previously, paroxetine and sertraline possess moderate affinity (<50 nmol/L) for the human norepinephrine transporter and dopamine transporter, respectively. R-fluoxetine, unlike the other selective serotonin reuptake inhibitors, possesses moderate affinity (Ki=64 nmol/L) for the serotonin 2C receptor. Potential clinical correlates of these unique attributes of escitalopram and R-fluoxetine are discussed. (Biol Psychiatry 2001; 50: 345-350 " 2001 Society of Biological Psychiatry).

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citalopram Celexa
Citalopram inhibits L-type calcium channel current in rat cardiomyocytes in culture.

Hamplova-Peichlova J, Krusek J, Paclt I, Slavicek J, Lisa V, Vyskocil F.

Psychiatric Clinic, First Medical Faculty, Charles University, Prague, Czech Republic.

Selective serotonine reuptake inhibitors (SSRI) are believed to be less dangerous in the treatment of depressive disorder in comparison with tricyclic antidepressants (TCA) due to their relative lack of cardiotoxicity. Thus, we investigated the effect of citalopram (SSRI) on membrane electrophysiology in rat cardiomyocytes in tissue culture. The results were compared with those from amitriptyline (TCA). The whole-cell configuration patch-clamp technique was used. Both citalopram and amitriptyline exhibited the concentration-dependent inhibition of the L-type calcium channel current (ICa). Citalopram in concentrations of 3 microM and 10 microM inhibited peak calcium current by 2.7% and 8%, respectively. We demonstrated the same potency of citalopram and amitriptyline to inhibit ICa. These observations led us to conclude that citalopram and amitriptyline are drugs, which exhibit a similar potency for causing concentration-dependent inhibition of ICa.

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citalopram Celexa
The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats.

Mork A, Kreilgaard M, Sanchez C.

Department of Neurochemistry and Discovery ADME, H. Lundbeck A/S, Copenhagen, Denmark. arm lundbeck.com

The selective serotonin (5-HT) reuptake inhibitor, citalopram, is a racemic mixture of an S(+)- and R(-)-enantiomer, escitalopram and R-citalopram, respectively. The present study compares the effects of escitalopram, R-citalopram and citalopram on extracellular levels of 5-HT in the frontal cortex of freely moving rats. In addition, co-injection of escitalopram and R-citalopram (ratios 1:2 and 1:4) were assessed. In some experiments escitalopram and R-citalopram were infused into the frontal cortex by reverse microdialysis. Finally, the extracellular level of escitalopram in the frontal cortex was studied after administration of escitalopram alone or in combination with R-citalopram. Escitalopram (1.0-3.9 mg/kg, s.c.) produced a greater maximal increase in extracellular 5-HT than citalopram (2.0-8.0 mg/kg, s.c.). R-citalopram (15.6 mg/kg s.c.) did not affect the 5-HT levels. When co-injected, R-citalopram counteracted the escitalopram-induced increase in extracellular 5-HT levels. Local infusion of the two enantiomers into the frontal cortex produced a similar inhibitory response. R-citalopram did not influence the extracellular levels of escitalopram and therefore does not exert its effect via a pharmacokinetic interaction with escitalopram. In conclusion, the 5-HT-reuptake inhibitory activity of citalopram resides in escitalopram, and the R-enantiomer counteracts this effect. This observation would predict an improved clinical profile of escitalopram compared to citalopram.

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