paroxetine, Paxil
Solubilization and characterization of [3H]imipramine and [3H]paroxetine binding sites from calf striatum.

Rotondo A, Giannaccini G, Quattrone C, Marazziti D, Martini C, Cassano GB, Lucacchini A.

Institute of Psychiatry, University of Pisa, Italy.

The serotonin (5-HT) transporter from calf striatum cerebral membranes was solubilized with digitonin and characterized by gel exclusion chromatography. [3H]Imipramine and [3H]paroxetine were utilized as markers for labeling it. 3H-imipramine labels a high- and a low-affinity site on striatum membranes, whereas it binds to a single high-affinity site on the solubilized fraction. [3H]Paroxetine binds with the same affinity to a single site on both membranes and solubilized preparations. After gel exclusion chromatography of the solubilizate both [3H]imipramine and [3H]paroxetine bind on an identical fraction of 205 kDa molecular weight, with a similar maximum number of binding sites (Bmax). Our results suggest that both 3H-imipramine and [3H]paroxetine bind to a common site on the 5-HT transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7891847&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Further studies on platelet serotonin transporter binding in depression.

Nemeroff CB, Knight DL, Franks J, Craighead WE, Krishnan KR.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322-4990.

OBJECTIVE: There is an impressive literature implicating abnormalities in serotonergic neural systems in depression. Many investigators, but not all, have reported low numbers of platelet and brain serotonin (5-HT) transporter sites in drug-free depressed patients. In the present study the authors sought to determine whether the low platelet 5-HT transporter binding in depressed patients is due to previous antidepressant drug exposure. In addition, the binding of both [3H]imipramine and the more specific ligand [3H]paroxetine to the platelet 5-HT transporter was compared in drug-free depressed patients and age- and sex-matched normal comparison subjects. METHOD: In the first experiment blood samples were obtained from 12 depressed patients who had never received antidepressant drugs and 12 normal comparison subjects, and platelet 5-HT transporter binding was measured by using [3H]imipramine. In the second experiment blood samples were obtained from 28 drug-free depressed patients and 28 age- and sex-matched comparison subjects, and platelet 5-HT transporter binding was assessed by using both [3H]imipramine and [3H]paroxetine. RESULTS: In the first experiment the never-medicated depressed patients exhibited fewer platelet [3H]imipramine binding sites than did the comparison subjects. In the second experiment the drug-free depressed patients had fewer platelet binding sites for both [3H]imipramine and [3H]paroxetine than did the comparison subjects. CONCLUSIONS: The low number of platelet [3H]imipramine binding sites does not appear to be due to prior antidepressant drug exposure. The Bmax of platelet binding sites for both [3H]imipramine and [3H]paroxetine, ligands used to measure 5-HT transporter binding, is abnormally low in depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7943450&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Automated determination of paroxetine and its main metabolite by column switching and on-line high-performance liquid chromatography.

Hartter S, Hermes B, Szegedi A, Hiemke C.

Department of Psychiatry, University of Mainz, Germany.

An automated column-switching method coupled to isocratic high-performance liquid chromatography has been developed for simultaneous determination of blood levels of paroxetine and its nonconjugated main metabolite BRL 36610. The lower limits of detection were 9-15 nmol/L (3-5 ng/ml) and linearity between drug concentration and detector response was found for 0-1,500 nmol/L (0-500 ng/ml). The method could be applied to the analysis of serum samples obtained from depressed patients who were treated with daily oral doses of 20 or 40 mg of paroxetine. After the 20-mg dose, the mean blood level of paroxetine was 69 nM (23 ng/ml), whereas the metabolite BRL 36610 was detectable in only one of 5 samples. Co-medication of paroxetine with imipramine increased the blood levels of imipramine, desipramine, and paroxetine thus indicating drug interactions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7974631&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Studies of a neurochemical link between depression, anxiety, and stress from [3H]imipramine and [3H]paroxetine binding on human platelets.

Iny LJ, Pecknold J, Suranyi-Cadotte BE, Bernier B, Luthe L, Nair NP, Meaney MJ.

Department of Psychiatry, Douglas Hospital Research Centre, McGill University, Montreal, Quebec.

We measured platelet [3H]imipramine and [3H]paroxetine binding in patients with major depression (n = 11), dysthymia (n = 9), generalized anxiety (n = 18) and panic disorder (n = 10), and in healthy controls (n = 13). The [3H]imipramine binding capacity (Bmax) was lower in all patient groups; [3H]paroxetine binding was reduced in anxiety disorders, however, decreases in depression and dysthymia were not significant. There were no differences in the affinity constant (Kd) for either radioligand. We also examined the effects of examination stress on platelet binding in medical students. Compared to after vacation, when binding was similar to controls, [3H]imipramine (n = 19) and [3H]paroxetine (n = 14) Bmax values were significantly decreased during examinations and similar to patient values. Examinations were also associated with an increase in plasma cortisol levels. These findings suggest that there is a neurochemical link between depression, anxiety, and stress, and that disturbances in neurochemical functioning may be associated with specific symptomatology, independent of psychiatric diagnosis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7993954&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Platelet 3H-paroxetine binding in control subjects and depressed patients: relationship to serotonin uptake and age.

Nankai M, Yamada S, Yoshimoto S, Watanabe A, Mori H, Asai K, Toru M.

Department of Neuropsychiatry, Faculty of Medicine, Tokyo Medical and Dental University, Japan.

3H-paroxetine is regarded as a better ligand for the serotonin (5-hydroxytryptamine; 5-HT) uptake site than 3H-imipramine. In the present study, platelet 14C-5-HT uptake and 3H-paroxetine binding were simultaneously measured in 12 control subjects. There was a significant positive correlation between the individual Bmax value for 3H-paroxetine binding and the Vmax value for 14C-5-HT uptake. Platelet 3H-paroxetine binding was also determined in 21 drug-free patients who satisfied DSM-III-R criteria for major depression and 21 control subjects. A negative correlation was found between the Bmax values for 3H-paroxetine binding with age in control subjects. There was no change in 3H-paroxetine binding in depressed patients compared with control subjects. Our results indicated that 3H-paroxetine was a good ligand for evaluating 5-HT uptake sites, and the influence of age ought to be taken into consideration in the study of 3H-paroxetine binding. The present study indicated that there was no change in 5-HT uptake sites in platelets from depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8022949&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Occupancy of the serotonin transporter by fluoxetine, paroxetine, and sertraline: in vivo studies with [125I]RTI-55.

Scheffel U, Kim S, Cline EJ, Kuhar MJ.

Johns Hopkins University School of Medicine, Department of Radiology, Baltimore, MD 21205.

[125I]RTI-55 was used tracer doses to label serotonin (5-HT) transporters in vivo in the mouse brain. Fluoxetine, paroxetine, and sertraline, potent antidepressants and selective inhibitors of serotonin transporter sites, were administered in various doses and at various times. The doses and times that result in significant binding of the drugs to transporters correspond to doses and times where they are reported to have physiological effects. Estimates of occupancy rate and duration of binding to serotonin transporters were made. The rate of occupancy of the 5-HT transporter site was fastest for sertraline, intermediate for paroxetine and slowest for fluoxetine. Similarly, the duration of occupancy was significantly shorter for sertraline and paroxetine (approximately 10 h) than for fluoxetine (approximately 50 h). The results indicate that in competition studies, [125I]RTI-55 can be used to identify doses of drugs that are physiologically effective, to determine their relative rate of occupancy, and most importantly, to measure the residency time on the central serotonin transporter in vivo.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8059336&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
D2 dopamine receptor gene polymorphism: paroxetine and social functioning in posttraumatic stress disorder.

Lawford BR, McD Young R, Noble EP, Kann B, Arnold L, Rowell J, Ritchie TL.

Greenslopes Private Hospital, Queensland, Brisbane, Australia.

This study examined whether allelic status of the D2 dopamine receptor (DRD2) gene was associated with response to a selective serotonin reuptake inhibitor, paroxetine, in the treatment of posttraumatic stress disorder (PTSD). Sixty-three Caucasian war veterans with combat-related PTSD were treated with paroxetine for 8 weeks. Patients were assessed at baseline and at follow-up using the General Health Questionnaire-28 (GHQ). TaqI A DRD2 alleles were determined by PCR. Before paroxetine treatment, patients with the DRD2 A1+ allele (A1A2 genotype) compared to those with the A1- allele (A2A2 genotype) had higher total GHQ psychopathological scores (P=0.040) and higher GHQ subscale scores for anxiety/insomnia (0.046), social dysfunction (P=0.033) and depression (P=0.011). In an intention-to-treat analysis, paroxetine was associated with significant improvement in total GHQ scores (P=0.014) and in the factor scores of social dysfunction (P=0.033), anxiety (P=0.009) and depression (P=0.026). Furthermore, there was a significant allele by time interaction on the social dysfunction scale, with A1+ allelic patients showing significant improvement in social functioning compared to A1- allelic patients (P=0.031), an effect independent of changes in depression or anxiety. This suggests changes in social functioning induced by paroxetine may be, in part, mediated via D2 dopamine receptors. The DRD2 A1 allele may prove to be a useful marker to assist clinicians in predicting which patients with PTSD are likely to obtain improvements in social functioning with paroxetine treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12957328&dopt=Abstract paroxetine, Paxil, Paxil CR