paroxetine, Paxil
Platelet serotonergic functions and light therapy in seasonal affective disorder.

Stain-Malmgren R, Kjellman BF, Aberg-Wistedt A.

Department of Psychiatry, Institution of Clinical Science, Karolinska Institute, St. Goran's Hospital, Stockholm, Sweden.

We investigated platelet 14C-serotonin uptake and platelet [3H]LSD and [3H]paroxetine binding in 11 patients with seasonal affective disorder (SAD). Patients were reinvestigated after light therapy, applied at 07.00-09.00 h for 10 consecutive days. The degree of depression was rated before and after light therapy using the Comprehensive Psychopathological Rating Scale (CPRS). Baseline data in patients were compared with data from a control group consisting of 11 age- and sex-matched healthy volunteers. Seven patients responded to light therapy with a > 50% reduction in CPRS scores. In non-responders, the reduction in CPRS was 24.7 +/- 5.5%. There was a significant inverse correlation (P = 0.014) between Km for platelet 14C-serotonin uptake and CPRS scores. Patients had significantly higher Bmax for platelet [3H]LSD binding (P = 0.04) and significantly lower Bmax for platelet [3H]paroxetine binding (P = 0.016). There was a strong, multiple correlation between Bmax for [3H]LSD, as the dependent variable, and Km, Vmax and Bmax for [3H]paroxetine binding in patients (P < 0.0001) but not in controls. Responders to light therapy had significantly higher Km (P = 0.023) and significantly lower Bmax for [3H]paroxetine binding (P = 0.028) than non-responders. Bmax for [3H]paroxetine binding increased significantly to normal levels after light therapy. The results indicate that SAD is associated with aberrations in the serotonin uptake mechanism. The enhanced 5-HT2-receptor density may reflect a consequential up-regulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9657420&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Simultaneous determination of human plasma levels of citalopram, paroxetine, sertraline, and their metabolites by gas chromatography-mass spectrometry.

Eap CB, Bouchoux G, Amey M, Cochard N, Savary L, Baumann P.

Departement Universitaire de Psychiatrie Adulte, Hopital de Cery, Prilly-Lausanne, Switzerland. Chin.Eap inst.hospvd.ch

A gas chromatography-mass spectrometry method is presented which allows the simultaneous determination of the plasma concentrations of the selective serotonin reuptake inhibitors citalopram, paroxetine, sertraline, and their pharmacologically active N-demethylated metabolites (desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline) after derivatization with the reagent N-methyl-bis(trifluoroacetamide). No interferences from endogenous compounds are observed following the extraction of plasma samples from six different human subjects. The standard curves are linear over a working range of 10-500 ng/mL for citalopram, 10-300 ng/mL for desmethylcitalopram, 5-60 ng/mL for didesmethylcitalopram, 20-400 ng/mL for sertraline and desmethylsertraline, and 10-200 ng/mL for paroxetine. Recoveries measured at three concentrations range from 81 to 118% for the tertiary amines (citalopram and the internal standard methylmaprotiline), 73 to 95% for the secondary amines (desmethylcitalopram, paroxetine and sertraline), and 39 to 66% for the primary amines (didesmethylcitalopram and desmethylsertraline). Intra- and interday coefficients of variation determined at three concentrations range from 3 to 11% for citalopram and its metabolites, 4 to 15% for paroxetine, and 5 to 13% for sertraline and desmethylsertraline. The limits of quantitation of the method are 2 ng/mL for citalopram and paroxetine, 1 ng/mL for sertraline, and 0.5 ng/mL for desmethylcitalopram, didesmethylcitalopram, and desmethylsertraline. No interferences are noted from 20 other psychotropic drugs. This sensitive and specific method can be used for single-dose pharmacokinetics. It is also useful for therapeutic drug monitoring of these three drugs and could possibly be adapted for the quantitation of the two other selective serotonin reuptake inhibitors on the market, namely fluoxetine and fluvoxamine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9679303&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Validated chiral high-performance liquid chromatographic method for the determination of trans-(-)-paroxetine and its enantiomer in bulk and pharmaceutical formulations.

Ferretti R, Gallinella B, La Torre F, Turchetto L.

Istituto Superiore di Sanita, Laboratorio di Chimica del Farmaco, Rome, Italy.

A stereospecific high-performance liquid chromatography method for the determination of trans-(-)-paroxetine and its enantiomer in bulk raw material and pharmaceutical formulations was developed and validated. The enantiomeric separation was achieved, without any derivatization, on a carbamate derivative-based column (Chiralpak AD). The effect of the organic modifiers, 2-propanol and ethanol, in the mobile phases was optimised to obtain enantiomeric separation. Limits of detection and quantitation of 2 and 6 ng, respectively, were obtained for both of the enantiomers. The linearity was established in the range of 5-41 microg for trans-(-)-paroxetine and in the range of 10-160 ng for trans-(+)-paroxetine. The accuracy of the method was 102.3% (mean value) for trans-(-)-paroxetine and 99.9% (mean value) for trans-(+)-paroxetine. For the precision (repeatability), a relative standard deviation value of 1.5% (mean value) for trans-(-)-paroxetine and of 2.1% (mean value) for trans-(+)-paroxetine was found. The method is capable of determining a minimum limit of 0.2% of trans-(+)-isomer in commercial samples.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9686883&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Combining pindolol and paroxetine in an animal model of chronic antidepressant action--can early onset of action be detected?

Cryan JF, McGrath C, Leonard BE, Norman TR.

Department of Psychiatry, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.

The realisation that pindolol may accelerate the effects of some antidepressant drugs in clinical trials has added extra impetus to the search for faster acting antidepressants. Currently, no animal model of depression can identify potential faster acting antidepressant drugs or drug combinations. In this study, we investigate the effects of combining pindolol (2 mg/kg, s.c., bid) with the antidepressant paroxetine (2.5 mg/kg, i.p., bid) in the olfactory bulbectomised rat, an animal model of chronic (but not acute) antidepressant activity. Ambulation scores were measured in separate groups of rats, following 3, 7 and 14 days of treatment. Further, we simultaneously study adaptive changes in 5-HT1A receptor function, utilising alterations in the hypothermic response to the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). Pindolol in combination with paroxetine attenuated the hypothermic effects of 8-OH-DPAT as early as 3 days with a full reversal evident following 7 days, whereas paroxetine alone did so after 14 days only. Likewise, paroxetine alone reversed the olfactory bulbectomy-induced hyperactivity in the open field following 14 days of treatment only, this being the normal time of an 'antidepressant' response in this model. However, the group treated with both paroxetine and pindolol failed to reverse the hyperactive response. This suggests that a factor intrinsic to pindolol antagonises the behavioural effects of paroxetine in the olfactory bulbectomised rat. It also demonstrates that the reversal of this aspect of the olfactory bulbectomy-induced behavioural syndrome is insensitive to the potential faster onset of antidepressant action induced by pindolol. The ability of the combination group to attenuate the hypothermic effects of 8-OH-DPAT much faster further emphasises the role of the 5-HT1A receptor in the mechanism of action of antidepressants and as a target for the development of faster acting antidepressants. However, an animal model sensitive to the effects of any such compound and the actions of pindolol remains elusive.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9718263&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Contrasting effects of chronic paroxetine on 5-HT1A control of dorsal raphe cell firing and 5-HT release.

Davidson C, Stamford JA.

Academic Department of Anaesthesia and Intensive Care, St Bartholomew's and the Royal London School of Medicine and Dentistry, Royal London Hospital, UK.

To test the role of 5-HT1A receptors in the action of antidepressants, we investigated the effect of chronic paroxetine (10 mg/kg, p.o. for 21 days) on functional assays of 5-HT1A sensitivity. We constructed cumulative concentration response curves to the selective 5-HT1A agonist (+)-8-OH-DPAT on both extracellular recordings of 5-HT neurones and electrically stimulated 5-HT release in dorsal raphe brain slices. Chronic paroxetine desensitized the 5-HT1A receptors controlling firing, with an increase in EC50 from 10.7 nM to 46.2 nM 8-OH-DPAT. Chronic paroxetine did not, however, desensitize the 5-HT1A receptors controlling 5-HT release but increased the 8-OH-DPAT Emax from 54.9% to 79.2% inhibition of 5-HT release. These data suggest that there are either two distinct populations of 5-HT1A receptors or separate second messenger systems, one controlling 5-HT release and another influencing firing. Furthermore chronic paroxetine treatment can differentially modulate these different populations.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9721928&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Pharmacologic factors associated with transient neonatal symptoms following prenatal psychotropic medication exposure.

Oberlander TF, Misri S, Fitzgerald CE, Kostaras X, Rurak D, Riggs W.

Department of Pediatrics, Centre for Community Child Health Research, University of British Columbia, L408-4480 Oak Street, Vancouver, BC, Canada V6H 3V4. toberlander cw.bc.ca

BACKGROUND: Selective serotonin reuptake inhibitor antidepressants (SSRIs) and benzodiazepines are frequently used to treat maternal depression and anxiety disorders during pregnancy. Recent reports suggest that prenatal SSRI exposure is associated with a neonatal discontinuation syndrome. It remains unclear whether these symptoms are directly related to SSRI exposure alone or are due to concurrent pharmacologic factors. Also, this study explores relationships between neonatal outcomes and medication levels during pregnancy, at delivery, and in the newborn period. METHOD: This study sought to compare newborn behavior following second and third trimester exposure to either single-agent SSRIs (group 1) or SSRIs combined with clonazepam (group 2). A prospective cohort of mothers and their infants (N = 46) who had received SSRI medication alone or in combination with clonazepam were studied from June 1996 through June 2000 and compared with a nonexposed control group (N = 23). Infants were assessed in the newborn period for signs suggestive of a "discontinuation syndrome." Maternal drug levels were measured during the pregnancy and at delivery. Infant drug levels from cord blood and at day 2 of life were also obtained. RESULTS: Overall, 30% of the exposed infants (groups 1 and 2, N = 14) showed symptoms of transient poor neonatal adaptation compared with 9% (N = 2) of control infants. In group 1, 25% had symptoms (fluoxetine N = 3; paroxetine N = 3; sertraline N = 1) and in group 2, 39% of infants had symptoms (paroxetine with clonazepam, N = 7). Symptoms were typically mild respiratory distress and, less commonly, hypotonia. Symptoms were self limited and not associated with other neonatal conditions. When paroxetine was combined with clonazepam, infants with symptoms had significantly elevated paroxetine levels when compared with similarly exposed infants without symptoms (p <.05). Among single-agent paroxetine-exposed infants, drug levels did not differ significantly between those with and without symptoms. Maternal dose of clonazepam was significantly higher (p <.05) during pregnancy and at delivery among symptomatic infants compared with nonsymptomatic infants. Developmental outcomes at 2 and 8 months of age did not differ between symptomatic and nonsymptomatic infants. CONCLUSION: While transient neonatal symptoms were found in infants after single-agent prenatal exposure to SSRIs and when paroxetine was combined with clonazepam, the addition of clonazepam appeared to alter paroxetine metabolism, leading to increased drug levels and risk for transient neonatal symptoms. These data highlight the importance of accounting for a variety of pharmacologic factors beyond single-agent SSRI exposure that may lead to poor neonatal adaptation. Further studies are needed with a larger sample of infants to determine the role of clonazepam and whether similar outcomes occur when exposure includes other SSRIs in combination with clonazepam.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15003078&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Selective serotonin reuptake inhibitor utilization patterns: consistency across research designs.

Hutchins DS, Klein EG, Signa WF, Young CH, Gregor KJ.

Outcomes Research, PCS Health Systems, Inc., Scottsdale, Arizona 85260-6719, USA.

We examined the impact of commonly applied selection criteria on the ability of patients who are initiating antidepressant therapy to reach a stable pattern, which was defined as receipt of only the initial agent at the initial dose for 90 or more consecutive days. Patients in a large US prescription database who initiated fluoxetine, paroxetine, or sertraline therapy between February and April of 1995 were categorized as with (typical design) and without (relaxed design) commonly applied selection criteria. The percentage of patients achieving a stable pattern was then determined. We found that this percentage was significantly higher with the relaxed design (typical, 28.8%; relaxed, 32.4%) and for patients initiating fluoxetine therapy (>5.5% higher than for those initiating paroxetine or sertraline therapy). The results for fluoxetine were consistent across designs, whereas comparisons between paroxetine and sertraline yielded mixed results. Therefore, the relative relationship of the stable pattern is robust across designs for fluoxetine but not for paroxetine and sertraline. Further, application of commonly applied selection criteria may make a sample less representative and reduce the measured rates of stable antidepressant use, potentially leading to underestimation of the benefits of pharmacotherapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9737838&dopt=Abstract paroxetine, Paxil, Paxil CR