paroxetine, Paxil
Effects of acute and chronic tianeptine administration on serotonin outflow in rats: comparison with paroxetine by using in vivo microdialysis.

Malagie I, Deslandes A, Gardier AM.

Laboratoire de Neuropharmacologie, UPRES EAD MENRT, Faculte de Pharmacie IFR-ISIT, Institut de Signalisation et Innovation Therapeutique, Universite Paris-Sud, F92296 Chatenay-Malabry, France.

Using in vivo microdialysis, we compared the effects of tianeptine (an antidepressant drug which, in marked contrast with other antidepressants, is thought to increase the uptake of serotonin (5-hydroxytryptamine, 5-HT) on extracellular 5-HT concentrations ([5-HT](ext)) in the frontal cortex and raphe nuclei of freely moving rats with those of paroxetine, a potent selective serotonin reuptake inhibitor. A single paroxetine dose (1 mg/kg, i.p.) increased [5-HT](ext) over baseline in the frontal cortex and raphe nuclei, respectively. A single administration of tianeptine (10 mg/kg, i.p.) did not change [5-HT(ext)] in the two brain regions studied. Repeated exposure to paroxetine (0.5 mg/kg) b.i.d. for 14 days induced a sixfold significant increase in basal [5-HT](ext) in the raphe nuclei. Administration of tianeptine (5 mg/kg) b.i.d. for 14 days did not affect 5-HT baseline concentrations. In rats chronically treated with either paroxetine or tianeptine, drug challenge did not alter area under the curve values. Thus, our in vivo data indicate that tianeptine and paroxetine do not exert a similar in vivo effect on the serotonergic system in rat brain.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10969144&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Serotonin transporter gene regulatory region polymorphism (5-HTTLPR), [3H]paroxetine binding in healthy control subjects and alcohol-dependent patients and their relationships to impulsivity.

Preuss UW, Soyka M, Bahlmann M, Wenzel K, Behrens S, de Jonge S, Kruger M, Bondy B.

Department of Psychiatry, Ludwig-Maximilians Universitat Munchen, Nussbaumstr 7, 80336, Munchen, Germany. up psy.med.uni-muenchen.de

The aim of this study was to investigate [3H]paroxetine binding and impulsivity in alcohol-dependent and age-matched control subjects in relation to a 5'-promoter region serotonin transporter (5-HTT) polymorphism (5-HTTLPR). Alcohol-dependent subjects were hypothesized to show a decreased number of bindings sites and a lower dissociation constant. 5-HTTLPR S-genotype carriers in both alcohol-dependent and control subjects were expected to show significantly fewer binding sites and a lower dissociation constant. Influences of impulsive traits, chronic daily alcohol intake, duration of alcohol dependence, age of onset and age on [3H]paroxetine binding were also investigated. Inpatients meeting DSM IV alcohol dependence criteria and of German descent were recruited to avoid ethnic stratification effects. One hundred and seventeen control subjects of similar social status were recruited from a town community. Blood samples were taken from both alcohol-dependent and control subjects to determine 5-HTTLPR genotypes using PCR of lymphocyte DNA, and to perform platelet [3H]paroxetine binding (binding capacity: B(max); and dissociation constant: K(D)). Impulsivity was assessed using the Barratt impulsiveness scale version 5 (BIS-5) in alcohol-dependent subjects only. Alcohol-dependent subjects were subdivided into low or high impulsivity groups using a median-split of the BIS-5 scale. The control group was slightly older than the alcohol-dependent group (not statistically significant). [3H]paroxetine binding was investigated in 72 control subjects and 72 patients, of which five patients met type 2 alcohol dependence criteria. Genotyping was carried out in all patients and control subjects. A significant influence of duration of alcohol dependence was found on the [3H]paroxetine binding K(D) but not B(max.) Neither alcohol-dependent nor control subjects showed any differences in B(max) or K(D). S-allele carriers did not show a decreased binding or lower dissociation constant. Furthermore, no significant interaction between B(max) and K(D) with either 5-HTTLPR genotype or impulsivity was revealed. This was the first study to investigate platelet [3H]paroxetine binding in alcohol-dependent and age-matched control subjects in relation to the 5-HTTLPR genotype. No differences concerning 5-HTTLPR-alleles were found in these groups Furthermore, no significant interaction between these parameters and impulsivity was shown in alcohol-dependent subjects. These results do not support previous results of altered [3H]paroxetine binding sites in alcohol-dependent subjects or 5-HTTLPR S-allele carriers. K(D) might be influenced by duration of alcohol dependence, but not sufficiently to yield differences between alcohol-dependent and control subjects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10980326&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Platelet reactivity in depressed patients treated with paroxetine: preliminary findings.

Musselman DL, Marzec UM, Manatunga A, Penna S, Reemsnyder A, Knight BT, Baron A, Hanson SR, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 1639 Pierce Dr, Suite 4000, Atlanta, GA 30322, USA.

BACKGROUND: Alterations in platelet reactivity have been previously posited to underlie the increased vulnerability of patients with depression to ischemic heart disease (IHD). The present study sought to determine whether the increased platelet reactivity associated with major depression is reduced after antidepressant treatment. METHODS: Patients diagnosed as having DSM-IV major depression (n = 15) (mean age, 37 +/- 7 years; range, 23-48 years) and 12 normal comparison subjects (mean age, 36 +/- 7; range, 23-48 years) were recruited. None of the controls or depressed group had evidence of IHD; 10 of 15 patients who were depressed had 1 or more traditional IHD risk factors. In vivo platelet activation, secretion, and dose-response aggregation of the controls and patients was measured after overnight bedrest under basal conditions, and after a mild exercise challenge. After 6 weeks of open-label treatment with the selective serotonin reuptake inhibitor paroxetine (20 mg/d), the patients with depression were readmitted and procedures of the first General Clinical Research Center admission repeated. RESULTS: In comparison with the control group, the depressed group exhibited greater procoagulant activity as detected by increased platelet binding of the monoclonal antibodies anti-ligand-induced binding site and GA6, and increased plasma concentrations of platelet factor 4 under basal conditions. After paroxetine treatment, the patients with depression exhibited significant reductions in all 3 parameters. CONCLUSIONS: Normalization of platelet activation is associated with paroxetine treatment of patients with depression. Because this study design did not allow for the determination of whether this effect of paroxetine on platelet function is caused by a direct effect of the drug or placebo or, alternatively, because of recovery from depression, studies containing a placebo and/or psychotherapy treatment arm may resolve this issue.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10986551&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Decrease in caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine.

Rosenberg DR, MacMaster FP, Keshavan MS, Fitzgerald KD, Stewart CM, Moore GJ.

Department of Psychiatry, Wayne State University, Detroit, USA. drosen med.wayne.edu

OBJECTIVE: To measure in vivo neurochemical changes in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD) before and after treatment. METHOD: Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the left caudate were conducted in 11 psychotropic drug-naive children, aged 8 to 17 years, with OCD before and after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor paroxetine (10-60 mg/day) and 11 healthy children aged 8 to 17 years. A different sample of 8 pediatric OCD patients and 8 healthy children had a 1H-MRS examination of occipital cortex. RESULTS: Caudate glutamatergic concentrations (Glx) were significantly greater in treatment-naive OCD patients than in controls but declined significantly after paroxetine treatment to levels comparable with those of controls. Decrease in caudate Glx was associated with decrease in OCD symptom severity. Occipital Glx did not differ between OCD patients and controls. CONCLUSIONS: These preliminary findings provide new evidence of Glx abnormalities in the caudate nucleus in pediatric OCD and suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate Glx.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10986805&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine influences respiration in rats: implications for the treatment of panic disorder.

Olsson M, Annerbrink K, Bengtsson F, Hedner J, Eriksson E.

Department of Pharmacology, Goteborg University, Box 431, SE 405 30 Goteborg, Sweden. marie.olsson pharm.gu.se

Since hyperventilation and shortness of breath are characteristic features of panic attacks, and since the attacks can be elicited by CO(2) inhalation, an involvement of central or peripheral chemoreceptors in the pathophysiology of panic disorder has been suggested. Prompted by clinical reports suggesting that the susceptibility to spontaneous as well as CO(2)-induced anxiety and hyperventilation is attenuated by serotonin reuptake inhibitors (SRIs), we undertook the present study in order to explore the possible effect of an SRI, paroxetine, on baseline respiration and CO(2)-induced hyperventilation in freely moving Wistar rats. A significant increase in baseline respiratory rate was seen both after 5 and 15 weeks of treatment with paroxetine. CO(2) exposure induced a dose-dependent increase in respiratory rate, but not tidal volume, in both paroxetine-treated rats and controls; this response was reduced after 15 weeks of paroxetine treatment, but not after 5 weeks of treatment. We suggest that an influence on the regulation of respiration may be of importance for the anti-panic effect of SRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14659984&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of a selective 5-hydroxytryptamine reuptake inhibitor on brain extracellular noradrenaline: microdialysis studies using paroxetine.

Hajos-Korcsok E, McTavish SF, Sharp T.

University Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, OX2 6HE, Oxford, UK.

The clinical efficacy of selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors (SSRIs) is normally attributed to their ability to increase brain 5-HT function although recent preclinical findings indicate that their selectivity for 5-HT over noradrenaline may be less evident in vivo. The present study investigated the effects of the SSRI, paroxetine, on extracellular levels of noradrenaline.Microdialysis was carried out in the hippocampus of the awake rat. In rats treated twice daily for 14 days with paroxetine (5 mg/kg s.c.), dialysate levels of noradrenaline showed a maintained two-fold increase compared to saline-injected controls. Paroxetine (5 mg/kg s.c.) administered once daily for 14 days did not cause a sustained increase in noradrenaline but levels showed a moderate (+58%) increase in response to a paroxetine challenge. Acute injection of paroxetine (5 mg/kg s.c.) did not elevate noradrenaline levels. Paroxetine (5 mg/kg s.c.) elevated dialysate 5-HT after both acute and repeated (twice daily for 14 days) treatment. The paroxetine-induced increase in noradrenaline (and 5-HT) was positively correlated with plasma concentrations of the drug, which were around the therapeutic range. In comparison to paroxetine, desipramine (10 mg/kg s.c.) caused a four-fold increase in dialysate noradrenaline (but did not change 5-HT) following repeated (once daily for 14 days) treatment and a two-fold increase at for acute treatment.In summary, despite its selectivity as a 5-HT reuptake inhibitor, paroxetine increased extracellular levels of noradrenaline in rat hippocampus following repeated administration. We discuss the possibility that a facilitation of noradrenaline function might be involved in the antidepressant effect of paroxetine, and possibly other SSRIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11050296&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Relationship between platelet serotonin uptake sites and measures of impulsivity, aggression, and craving among African-American cocaine abusers.

Patkar AA, Gottheil E, Berrettini WH, Hill KP, Thornton CC, Weinstein SP.

Division of Substance Abuse Programs, Department of Psychiatry and Human Behavior, Thomas Jefferson University, Philadelphia, PA 19107, USA. ashwin.patkar mail.tju.edu

We investigated whether platelet-tritiated paroxetine binding, a measure of serotonin uptake sites, and behavioral measures of impulsivity, aggression, and craving differed between cocaine-dependent subjects and controls and whether paroxetine binding was related to these behavioral measures. One hundred and five African-American cocaine-dependent outpatients and 44 African-American controls were studied. Tritiated paroxetine binding sites on platelets were assayed, and standardized assessments of impulsivity, aggression, and craving were performed. The Bmax values of paroxetine binding were significantly reduced among cocaine patients compared to controls. Cocaine patients showed significantly higher scores on certain measures of sensation seeking, impulsivity, and aggression as compared to controls. Furthermore, paroxetine binding showed a significant negative correlation with most measures of sensation seeking, impulsivity, and aggression--though not craving--among cocaine patients. Our findings indicate that densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14660157&dopt=Abstract paroxetine, Paxil, Paxil CR