paroxetine, Paxil
Relationship between brain serotonin transporter binding, plasma concentration and behavioural effect of selective serotonin reuptake inhibitors.

Hirano K, Kimura R, Sugimoto Y, Yamada J, Uchida S, Kato Y, Hashimoto H, Yamada S.

1Department of Biopharmaceutical Sciences and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.

The present study was undertaken to characterise the relationship between in vivo brain serotonin transporter (SERT) binding, plasma concentration and pharmacological effect of selective serotonin reuptake inhibitors (SSRIs) in mice. Oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at pharmacologically relevant doses exerted dose- and time-dependent binding activity of brain SERT as revealed by significant increases in K(D) for specific [(3)H]paroxetine binding, and the in vivo SERT-binding potency was in the order of paroxetine>>fluoxetine, sertraline>fluvoxamine.The time courses of brain SERT binding by SSRIs in mice were mostly in parallel to those of their plasma concentrations. Also, norfluoxetine (active metabolite) has been suggested to contribute largely to the long-lasting binding activity of brain SERT after the fluoxetine administration.Oral administration of each SSRI suppressed significantly the marble-burying behaviour with no change in locomotor activity in mice, and the extent and time course of suppression agreed well with those of brain SERT binding. Thus, the pharmacological potencies of SSRIs in the attenuation of marble-burying behaviour correlated significantly with their brain SERT binding activities.In conclusion, the present study has provided the first in vivo evidences to support that fluvoxamine, fluoxetine, paroxetine and sertraline orally administered bind to the pharmacologically relevant brain SERT in mice and that their SERT-binding characteristics is closely associated with the pharmacokinetics and inhibition of marble-burying behaviour.British Journal of Pharmacology advance online publication, 24 January 2005; doi:10.1038/sj.bjp.0706108.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15678084&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Improvement of dry mouth by replacing paroxetine with fluvoxamine.

Arima Y, Kubo C, Tsujimoto M, Ohtani H, Sawada Y.

Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.

OBJECTIVE: To present a case of improvement of paroxetine-induced dry mouth by substitution of fluvoxamine and analyze this case based on receptor occupancy theory. CASE SUMMARY: A 66-year-old woman with major depressive disorder had been treated with brotizolam 0.5 mg/day, flunitrazepam 2 mg/day, sulpiride 100 mg/day, bromazepam 2 mg/day, trazodone 25 mg/day, and paroxetine hydrochloride 10 mg/day. Although her psychological symptoms improved gradually, she complained of dry mouth. Paroxetine was replaced with fluvoxamine maleate 50 mg/day, and the dryness disappeared within a month. DISCUSSION: We calculated the time courses of muscarinic acetylcholine (mACh) receptor occupancy after oral administration of paroxetine and fluvoxamine at the treatment doses by using pharmacokinetic parameters obtained from the literature. The mACh receptor occupancy was estimated to be decreased from 0.22% to 0.020% by replacing paroxetine with fluvoxamine. CONCLUSIONS: The improvement of dry mouth observed after the replacement of paroxetine with fluvoxamine in this patient may have been due to a decrease in the mACh receptor occupancy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15701774&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine.

Szegedi A, Kohnen R, Dienel A, Kieser M.

Charite-Universitatsmedizin Berlin, Campus Benjamin Franklin, Department of Psychiatry and Psychotherapy, Eschenallee 3, 14050 Berlin, Germany.

OBJECTIVE: To investigate the efficacy of hypericum extract WS 5570 (St John's wort) compared with paroxetine in patients with moderate to severe major depression.Design Randomised double blind, double dummy, reference controlled, multicentre non-inferiority trial. SETTING: 21 psychiatric primary care practices in Germany. PARTICIPANTS: 251 adult outpatients with acute major depression with total score >/=22 on the 17 item Hamilton depression scale. INTERVENTIONS: 900 mg/day hypericum extract WS 5570 three times a day or 20 mg paroxetine once a day for six weeks. In initial non-responders doses were increased to 1800 mg/day hypericum or 40 mg/day paroxetine after two weeks. MAIN OUTCOME MEASURES: Change in score on Hamilton depression scale from baseline to day 42 (primary outcome). Secondary measures were change in scores on Montgomery-Asberg depression rating scale, clinical global impressions, and Beck depression inventory. RESULTS: The Hamilton depression total score decreased by mean 14.4 (SD 8.8) points, corresponding to 56.6% (SD 34.3%) of the baseline value, in the hypericum group and by 11.4 (SD 8.6) points (44.8% (SD 33.5%) of baseline value) in the paroxetine group (intention to treat analysis; similar results were observed in the per protocol analysis). The intention to treat analysis (lower one sided 97.5% confidence limit 1.5 points for the difference hypericum minus paroxetine) and the per protocol analysis (lower confidence limit 0.7 points) showed non-inferiority of hypericum and statistical superiority over paroxetine. The lower limits in both cases exceeded the pre-specified non-inferiority margin of -2.5 points and the superiority margin of 0. The incidence of adverse events was 0.035 and 0.060 events per day of exposure for hypericum and paroxetine, respectively. CONCLUSIONS: In the treatment of moderate to severe major depression, hypericum extract WS 5570 is at least as effective as paroxetine and is better tolerated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15708844&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Differences in serotonergic neurotransmission between rats displaying high or low anxiety/depression-like behaviour: effects of chronic paroxetine treatment.

Keck ME, Sartori SB, Welt T, Muller MB, Ohl F, Holsboer F, Landgraf R, Singewald N.

Max Planck Institute of Psychiatry, Munich, Germany.

Abstract Disturbances in serotonergic neurotransmission have been suggested to be closely interlinked with hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, and are likely to be involved in the pathophysiology of anxiety disorders and major depression. We therefore investigated markers of serotonergic transmission and their modulation by chronic paroxetine in rats selectively bred for high (HAB) or low (LAB) anxiety-related behaviour, both under basal conditions and in response to emotional stress. Hippocampal serotonin 1 A (5-HT(1A)) receptor mRNA expression was reduced in HAB rats, whereas 5-HT concentrations in hippocampal microdialysates did not differ between HAB and LAB rats under basal conditions. In the hippocampus, overall expression of serotonin transporter binding sites was increased in HAB compared with LAB rats. Exposure to emotional stress failed to increase intrahippocampal 5-HT release in HAB rats whereas LAB rats displayed a physiological, albeit small rise. Chronic paroxetine treatment markedly increased the stress-induced rise in hippocampal 5-HT in HAB, but not LAB rats. This effect may be (at least in part) related to a greater down-regulation of hippocampal serotonin transporter binding sites by paroxetine in HABs compared with LABs, while 5-HT(1A) receptor expression remained unaffected in this brain area. The findings indicate reduced hippocampal serotonergic transmission in HAB rats as compared with LAB rats, which is evident both at the presynaptic (5-HT release) and the postsynaptic (5-HT(1A) receptor) level. Chronic paroxetine enhanced the presynaptic responsivity in HAB rats, but not LAB rats, pointing to a preferential efficacy of paroxetine in rats with enhanced anxiety/depression-related behaviour.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15715667&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of chronic selective serotonin reuptake inhibitors on 8-OH-DPAT-induced facilitation of ejaculation in rats: comparison of fluvoxamine and paroxetine.

de Jong TR, Pattij T, Veening JG, Waldinger MD, Cools AR, Olivier B.

Department of Anatomy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

RATIONALE: Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) can delay ejaculation in humans, but the extent of this effect differs between SSRIs. The involvement of 5-HT(1A) receptors is likely, since 5-HT(1A) receptor agonists accelerate ejaculation and chronic SSRI treatment is thought to desensitize 5-HT(1A) receptors. OBJECTIVES: This study was conducted to examine the effects of chronic pretreatment with the SSRIs fluvoxamine and paroxetine on the facilitation of ejaculation induced by the 5-HT(1A) receptor agonist 8-OH-DPAT. METHODS: Sexually experienced Wistar rats with normal ejaculatory behavior were treated for 22 days with vehicle, fluvoxamine (30 mg/kg/day), or paroxetine (10 or 20 mg/kg/day, p.o.). On day 22, rats received a challenge with saline or 8-OH-DPAT (0.4 mg/kg, s.c.). Sexual behavior was tested on days 1, 8, 15, and 22 of the SSRI-treatment. RESULTS: Treatment with both doses of paroxetine, but not fluvoxamine, delayed ejaculation. 8-OH-DPAT strongly accelerated ejaculation under vehicle conditions. Pretreatment with paroxetine reduced the effects of 8-OH-DPAT on ejaculation in a dose-dependent manner and more strongly than fluvoxamine. CONCLUSIONS: SSRIs affect 5-HT(1A) receptors involved in ejaculation. The degree to which this occurs, with paroxetine exerting a stronger effect than fluvoxamine, might determine the extent of SSRI-induced delayed ejaculation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15719219&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Antidepressant-Induced Sweating (April).

Marcy TR, Britton ML.

Department of Pharmacy: Clinical and Administrative Sciences, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, OK.

OBJECTIVE: To report a case of excessive sweating probably caused by paroxetine, review the literature on antidepressant-induced sweating, and provide recommendations for the management of antidepressant-induced sweating. CASE SUMMARY: A 59-year-old white female presented to a pharmacist-staffed pharmacotherapy clinic with episodes of excessive sweating. The episodes occurred primarily on her head and back of the neck. Other etiologies were ruled out and paroxetine was discontinued. Paroxetine had been initiated at least 7 months prior to the reporting of symptoms. Sweating symptoms gradually improved until resolution 5 weeks following discontinuation of paroxetine. The Naranjo probability scale indicated a causal relationship is probable. DISCUSSION: Excessive sweating has been associated with antidepressants including tricyclic antidepressants, selective serotonin-reuptake inhibitors, and venlafaxine. In some patients, these symptoms require therapeutic intervention such as dose reduction, antidepressant substitution, antidepressant discontinuation, or addition of an agent to control sweating. Agents that have been reported successful in controlling the sweating include benztropine and cyproheptadine. CONCLUSIONS: We recommend a patient-specific approach for the management of antidepressant-induced sweating. First, consider dose reduction or a trial off antidepressant medication. In patients in whom this is inappropriate or ineffective, substitution of another antidepressant should be considered. If episodes of excessive sweating persist, consider treatment of sweating symptoms with benztropine or cyproheptadine in the absence of contraindications.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15728327&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Efficacy screening trials of paroxetine, pentoxifylline, riluzole, pramipexole and venlafaxine in cocaine dependence.

Ciraulo DA, Sarid-Segal O, Knapp CM, Ciraulo AM, Locastro J, Bloch DA, Montgomery MA, Leiderman DB, Elkashef A.

Division of Psychiatry, Boston University School of Medicine and VA Boston Healthcare System Medication Development Research Unit (MDRU), Boston, MA, USA.

ABSTRACT Aims The two studies presented here were conducted to assess the efficacy of paroxetine, pentoxifylline, riluzole, venlafaxine and pramipexole as medications for the treatment of cocaine dependence. Design A multi-arm, modified blinded, placebo-controlled design was used. Setting The studies were conducted at the Boston VA Healthcare System and the Boston University School of Medicine Medication Development Research Unit (MDRU). Participants Participants met criteria for cocaine dependence during a 2-week screening period. Intervention Following random assignment to one of the treatment groups, subjects received active medication or placebo for 8 weeks in combination with cognitive behavioral counseling. In the first study the efficacy of the antidepressant paroxetine (20 mg daily), the phosphodiesterase inhibitor pentoxifylline (1200 mg daily) and the glutamate release inhibitor riluzole (100 mg daily) was assessed. The antidepressant venlafaxine (150 mg daily) and the dopamine agonist pramipexole (1.5 mg daily) were evaluated in the second study. Measurements Urine benzoylecgonine (BE) concentrations, self-report of cocaine use and global impression scores served as primary outcome measures. Secondary measures included assessments of cocaine craving and psychiatric functioning. Adverse events were monitored during the treatment period. Findings None of the active medications produced greater reductions in urine BE concentrations over the treatment period than did placebo. There were trends for BE levels to become reduced in the pentoxifylline group during the first 4 weeks of treatment and for Addiction Severity Index (ASI) drug composite scores to be lower in the pentoxyfylline group at end-point compared to the placebo group. Significant within-group reductions in reported cocaine use and craving were found for all treatment groups, but none of the active medications were superior to placebo on these measures. The accuracy of self-reported cocaine use declined over the study period. Overall, the active medications were well tolerated. Conclusions This study does not support the use of paroxetine, pentoxifylline, riluzole, venlafaxine or pramipexole for the treatment of cocaine dependence. However, these results need to be interpreted with caution because of the small size and lack of homogeneity of the experimental groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15730346&dopt=Abstract paroxetine, Paxil, Paxil CR