Selective Serotonin Reuptake Inhibitors Paroxetine Research Articles

The guinea pig forced swim test as a new behavioral despair model to characterize potential antidepressants

Behavioral despair is a model of high predictivity for antidepressant activity in murids. For some drug targets, guinea pigs exhibit a higher homology to their human counterparts compared to murids. In this paper, we established a model of behavioral despair namely, the forced swim test (FST) in guinea pigs. Male guinea pigs underwent the FST similar to rats. Animals received intraperitoneal injections of either vehicle or drugs 24, 4, and 0.5 h before testing. We tested the tricyclic antidepressants desipramine and amitriptyline, the monoamine oxidase inhibitor tranylcypromine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, and the neurokinin 1 (NK(1)) receptor antagonist, L-733,060, and for comparison the antipsychotic clozapine and the stimulant methamphetamine. Desipramine (> or =3 mg/kg) and amitriptyline (>10 mg/kg) increased the latency to immobility (LTI) to greater than 230 s, and tranylcypromine (10 mg/kg) it to greater than 190 s. Paroxetine (>0.3 mg/kg) and fluoxetine (>10 mg/kg) also increased LTI significantly but only to greater than 120 s. Methamphetamine (3 mg/kg) completely eliminated immobility, whereas clozapine (5-20 mg/kg) had no effect. L-733,060 (10 mg/kg) increased LTI to 270 s. Doses producing significant effects in FST were investigated in the open field. Antidepressants did not affect locomotion, whereas methamphetamine induced hyperlocomotion. We demonstrate the suitability of a modified procedure of the FST for a nonmurid species: the guinea pig. Known antidepressants showed similar effects as in rats and mice. It is interesting to note that the NK(1) antagonist L-733,060 increased forced swimming, suggesting its antidepressant potential. Thus, the guinea pig FST allows the study of antidepressant activity also in NK(1) antagonists that cannot be studied appropriately in murids.

Selective serotonin reuptake inhibitors—A new modality for the treatment of lymphoma/leukaemia?

Selective serotonin reuptake inhibitors (SSRIs) have recently been reported to specifically kill malignant cells of B-lymphoid origin, i.e., cells derived from Burkitt lymphoma. Accordingly, SSRIs have been proposed as lead compounds in the development of new approaches to the treatment of lymphoma/leukaemia. Here we attempted to dissect the underlying signaling pathways by comparing susceptible and resistant cell lines. However, we found that all cell lines investigated underwent apoptotic cell death when exposed to SSRI concentrations exceeding 10 μM regardless of whether the cell lines were derived from B- (e.g., Namalwa, Ramos, Daudi, RL7), T-lymphoid tumors (e.g., Molt-4, Jurkat, CCRF-CEM) or other sources. The structure–activity relationship readily distinguished the pro-apoptotic and growth inhibitory effect of SSRIs from their eponymous action (blockage of the serotonin transporter): acetylation of the SSRIs fluvoxamine and paroxetine abrogated the ability of these compounds to inhibit 5HT-uptake, but did not impair their cytotoxic action. Based on these data we conclude that (i) SSRIs inhibit growth of transformed cells, but that (ii) this effect is neither specific for malignant cells nor specific for any particular cellular subset. (iii) The pro-apoptotic effect of SSRIs (at μM concentrations) is unrelated to their principal pharmacological action, i.e., inhibition of serotonin uptake (at nM concentrations). SSRIs or improved versions thereof are therefore unlikely to represent useful lead compounds for inducing apoptosis in B-cell derived tumors: the underlying mechanism is not confined to any specific cell lineage.

Quantification of Eight New Antidepressants and Five of their Active Metabolites in Whole Blood by High-Performance Liquid Chromatography-Tandem Mass Spectrometry

A liquid chromatography-tandem mass spectrometry method is described for the blood determination of selective serotonin reuptake inhibitors (fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram), serotonin noradrenaline reuptake inhibitors (milnacipram and venlafaxine), a noradrenergic and specific serotoninergic antidepressant (mirtazapine) and five of their active metabolites (norfluoxetine, desmethylcitalopram, didesmethylcitalopram, desmethylvenlafaxine, and desmethylmirtazapine). After a liquid-liquid extraction from blood, the compounds and the internal standard (methylrisperidone) were eluted on a XTerra RP18 column with a gradient of acetonitrile/ammonium formate buffer 4 mmol/L pH 3.2. They were then detected by electrospray ionization mass spectrometry with multiple reaction monitoring mode. The calibration curves were linear over the range 5-500 ng/mL (20-2000 ng/mL for venlafaxine and desmethylvenlafaxine). The limit of quantification was set at 5 ng/mL for each compound (except for venlafaxine and desmethylvenlafaxine: 20 ng/mL). The bias were lower than 12%. Intraday and interday precisions, expressed as variation coefficient, were lower than 11%. The extraction recoveries were between 70 and 90% except for desmethylmirtazapine, desmethylvenlafaxine, milnacipram, and didesmethylcitalopram. This specific and sensitive method allows management of intoxication and is suitable for the routine determination of antidepressants in forensic investigations.

Antidepressants induce cellular insulin resistance by activation of IRS-1 kinases

Certain selective serotonin reuptake inhibitors (SSRIs) induce the clinical and biochemical manifestations of a metabolic syndrome by as yet unknown mechanism. Here we demonstrate that incubation (1 h) of rat hepatoma Fao cells with the SSRIs paroxetine and sertraline, but not with the atypical antipsychotic drug olanzapine, inhibited the insulin-stimulated Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1) with half-maximal effects at ∼ 10 μM. This inhibition correlated with a rapid phosphorylation and activation of a number of Ser/Thr IRS-1 kinases including JNK, S6K1, ERK and p38 MAPK, but not PKB (Akt). JNK appears as a key player activated by SSRIs because specific JNK inhibitors partially eliminated the effects of these drugs. The SSRIs induced the phosphorylation of IRS-1 on S307 and S408, which inhibits IRS-1 function and insulin signaling. These results implicate selected SSRIs as inhibitors of insulin signaling and as potential inducers of cellular insulin resistance.

Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype

Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

Immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) on human T lymphocyte function and gene expression

Antidepressants have an antiproliferative effect in some cell lines. Depression may be associated with activation of some pro-inflammatory cytokines. Therefore, we evaluated the ex-vivo immunomodulatory effect of selective serotonin reuptake inhibitors (SSRIs) in T cells. We found that the SSRIs, paroxetine and sertraline decreased T-cell viability with IC50 around 10 μM. The inhibition obtained with exposure to the SSRIs was more pronounced than that achieved with dexamethasone. Moreover, these SSRIs inhibit the secretion of the TH1 factor-tumor necrosis factor(TNF)α from the cells. On the molecular level, the SSRIs suppressed signal transducer and activator of transcription 3 (Stat3) and cyclooxygenase(Cox)2 protein expression. The inhibitory effects were accompanied by alterations in gene expression as assessed in the gene array. These findings reveal an immunomodulatory effect of the SSRIs paroxetine and sertraline in human T cells. The clinical implications of our findings merit further investigation.

Paroxetine and congenital malformations: Meta-Analysis and consideration of potential confounding factors

Background:Antidepressants have been commonly used by women of childbearing age. Recent studies suggest that paroxetine, a selective serotonin reuptake inhibitor (SSRI), might specifically increase teratogenic risk. Objectives:The purpose of this study was to quantify first-trimester exposure to paroxetine and birth defects and examine potential sources of bias in the in utero or postnatal detection of more congenital malformations among women with depression. We also sought to examine whether paroxetine was used for the same indications as other SSRIs among pregnant women. Methods:This meta-analysis was designed to quantify malformation rates associated with the use of paroxetine. A search of the literature from 1985 to 2006 (English language) found in MEDLINE, EMBASE, REPROTOX, Scopus, and Biological Abstracts was conducted using the following terms: pregnancy outcome, congenital or fetal AND anomalies, malformations, cardiac/heart defects, AND selective serotonin reuptake inhibitors, paroxetine, and Paxil. Administrative databases of medication and medical services use in the Province of Quebec, Canada, were used to calculate the rates of ultrasound and echocardiogram in pregnancy and infancy in women/infants exposed to SSRIs and to compare the indications for general SSRI use versus paroxetine use. Results:Based on the studies analyzed, first-trimester paroxetine exposure was associated with a significant increase in the risk for cardiac malformation (odds ratio [OR], 1.72; 95% CI, 1.22-2.42). Women using antidepressants in pregnancy had a 30% higher rate of utilization of ultrasound in pregnancy. Infants of women who received SSRIs underwent approximately twice as many echocardiograms in the first year of life compared with children of women who used nothing. Significantly more women receiving paroxetine used the drug for anxiety or panic than women receiving other SSRIs (OR, 4.11; 95% CI, 2.39–7.08). Conclusions:Based on the results of this metaanalysis, first-trimester exposure to paroxetine appears to be associated with a significant increase in the risk for cardiac malformation. However, a detection bias cannot be ruled out as contributing to the apparent increased detection of cardiovascular malformation of children exposed in utero to paroxetine. A significantly greater number of women were using paroxetine for anxiety or panic when compared with women using other SSRIs.

Patient Compliance With SSRIs and Gabapentin in Painful Diabetic Neuropathy

Anticonvulsants are widely used for treatment of painful diabetic neuropathy. Selective serotonin reuptake inhibitors (SSRIs) are not first-line drugs but are commonly prescribed medicines for chronic pain. The majority of patients are hesitant to use these drug groups, thus their compliance remains an issue. To compare patient compliance and the effectiveness of 2 SSRIs (paroxetine or citalopram) and 1 anticonvulsant (gabapentin) in patients with painful diabetic neuropathy. This was a 6 months prospective trial in 101 patients with painful diabetic neuropathy and minimum score of 2 on a pain intensity scale ranging of 0 to 4. Compliance was assessed with patient interviews and pill counts. Adverse events, early discontinuation or satisfaction with treatment were also evaluated. Patients receiving SSRIs reported greater satisfaction and fewer concerns of the side-effects with their treatment (P<0.05) compared with the patients taking gabapentin. There was statistically significant better mood in the SSRI group (P<0.05). Overall, 43.5% of those taking SSRIs noticed no effect on the pain control, 50% felt better, and 6.5% felt worse. Among the patients taking gabapentin, 51% felt better, 40.5% noticed no effect, and 8.5% felt worse. Finally, on the pill count, more patients on SSRIs (93.5%) than on gabapentin (82.9%) were taking over the 75% of their medication (P<0.05). The lack of negative effects on quality of life, the better compliance, and the comparable efficiency of SSRIs suggest that these drugs may be considered as alternative to gabapentin in painful diabetic neuropathy.

Managing Common Side Effects of SSRIs

&lt;h4&gt;Please click &lt;a href="~/link.aspx?_id=E2E51DAC44DF4DBD95FCB377C8DC5B7F&amp;amp;_z=z"&gt;here&lt;/a&gt; to read the letter to the editor. &lt;/h4&gt; &lt;h4&gt;EXCERPT &lt;/h4&gt; &lt;p&gt;The selective serotonin reuptake inhibitor (SSRI) antidepressant agents fluvoxamine (Luvox&lt;sup&gt;&amp;reg;&lt;/sup&gt;), fluoxetine (Prozac&lt;sup&gt;&amp;reg;&lt;/sup&gt;), paroxetine (Paxil&lt;sup&gt;&amp;reg;&lt;/sup&gt;), sertraline (Zoloft&lt;sup&gt;&amp;reg;&lt;/sup&gt;), citalopram (Celexa&lt;sup&gt;&amp;reg;&lt;/sup&gt;), and escitalopram (Lexapro&lt;sup&gt;&amp;reg;&lt;/sup&gt;) are among the most widely prescribed medications in the world. They are approved and used primarily for the treatment of depression and various anxiety disorders but are also commonly used for the treatment of other mental disorders and physical conditions (Sadock &amp;amp; Sadock, 2001). These drugs are generally viewed as being safe and well tolerated. Indeed, their superior safety and tolerability profile, compared with that of older-generation antidepressant drugs, greatly contributed to their explosive and widespread use during the past 2 decades. Nevertheless, the SSRIs (like all drugs) are not perfect. In this article, I will review some of the most common side effects and their management. &lt;/p&gt; &lt;h4&gt;ABOUT THE AUTHOR&lt;/h4&gt; &lt;p&gt;Dr. Howland is Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, Pittsburgh, Pennsylvania. &lt;/p&gt; &lt;p&gt;The author discloses that he has no significant financial interests in any product or class of products discussed directly or indirectly in this activity, including research support. &lt;/p&gt; &lt;p&gt;Address correspondence to Robert H. Howland, MD, Associate Professor of Psychiatry, University of Pittsburgh School of Medicine, Western Psychiatric Institute and Clinic, 3811 O&amp;rsquo;Hara Street, Pittsburgh, PA 15213; e-mail: &lt;a href="mailto:HowlandRH@upmc.edu"&gt;HowlandRH@upmc.edu&lt;/a&gt;. &lt;/p&gt;

Mixture and single‐substance toxicity of selective serotonin reuptake inhibitors toward algae and crustaceans

Selective serotonin reuptake inhibitors (SSRIs) are used as antidepressant medications, primarily in the treatment of clinical depression. They are among the pharmaceuticals most often prescribed in the industrialized countries. Selective serotonin reuptake inhibitors are compounds with an identical mechanism of action in mammals (inhibit reuptake of serotonin), and they have been found in different aqueous as well as biological samples collected in the environment. In the present study, we tested the toxicities of five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline) as single substances and of citalopram, fluoxetine, and sertraline in binary mixtures in two standardized bioassays. Test organisms were the freshwater algae Pseudokirchneriella subcapitata and the freshwater crustacean Daphnia magna. In algae, test median effect concentrations (EC50s) ranged from 0.027 to 1.6 mg/L, and in daphnids, test EC50s ranged from 0.92 to 20 mg/L, with sertraline being one of the most toxic compounds. The test design and statistical analysis of results from mixture tests were based on isobole analysis. It was demonstrated that the mixture toxicity of the SSRIs in the two bioassays is predictable by the model of concentration addition. Therefore, in risk assessment based on chemical analysis of environmental samples, it is important to include the effect of all SSRIs that are present at low concentrations, and the model of concentration addition may be used to predict the combined effect of the mixture of SSRIs.

The Potential for Clinically Significant Drug-Drug Interactions Involving the CYP 2D6 System: Effects with Fluoxetine and Paroxetine versus Sertraline

Patients taking antidepressants are more likely to also be taking multiple medications, increasing the risk of adverse drug-drug interactions (DDIs). Because of substantial inhibition of one or more cytochrome P450 (CYP) enzymes at therapeutic doses, the selective serotonin reuptake inhibitors fluoxetine, fluvoxamine, and paroxetine have a higher risk of CYP-mediated DDIs than citalopram, escitalopram, and sertraline, which do not substantially inhibit any CYP enzyme. Prescribing patterns in 2,779 Veterans Affairs (VA) patients who had a prescription for an antidepressant in the preceding year and a current prescription for at least one systemically active drug were analyzed to determine 1) prevalence of drug combinations with potential to cause CYP-mediated DDIs, 2) frequency of combinations of fluoxetine, paroxetine, or sertraline with drugs whose metabolism is principally dependent on CYP 2D6, and 3) use of reduced doses of CYP 2D6 substrate/drugs with narrow therapeutic indices in patients on fluoxetine or paroxetine compared with sertraline. In 2,779 patients, 55 pairs of drugs with the potential to cause CYP-mediated DDIs occurred in 300 patients (11%), but only 26 of the patients and 6 of the drug pairs were identified by the VA Drug Alert System. Of the 461 patients receiving fluoxetine and/or paroxetine, 39 (8%) were also receiving a CYP 2D6-model substrate/drug with a narrow therapeutic index, 14 (36%) of whom were receiving high enough doses to be at moderate to high risk of a serious DDI. VA patients on fluoxetine, paroxetine, and sertraline were equally likely to be on drugs whose metabolism is dependent on CYP 2D6, including drugs with narrow therapeutic indices. No differences were found in doses of tricyclic antidepressants (i.e., "victim" drugs), which have narrow therapeutic indices and serious dose-dependent toxicity, when co-prescribed with fluoxetine or paroxetine versus sertraline (i.e., "perpetrator" drugs), despite predictable differences in CYP 2D6-mediated clearance of these drugs.

Reversal of learned helplessness by selective serotonin reuptake inhibitors in rats is not dependent on 5-HT availability

Serotonin (5-HT) and 5-HT 1A receptors have been suggested to play a pivotal role in the mechanism of action of antidepressant drugs, particularly in the case of selective serotonin reuptake inhibitors (SSRIs). In the rat learned helplessness (LH) paradigm, a valid animal model of human depression, repeated treatment with the 5-HT 1A receptor agonist 8-OH-DPAT (0.125 and 0.5 mg/kg) and several classes of antidepressants such as the tricyclic agent desipramine (30 and 60 mg/kg), the monoamine oxidase inhibitor (MAOI) pargyline (60 mg/kg) and the SSRIs fluoxetine (15 and 30 mg/kg), paroxetine (15 and 30 mg/kg) and sertraline (30 mg/kg) improved behavioural deficit in helpless rats. The involvement of serotonergic mechanisms in the antidepressant-like effect of these agents was investigated using the selective 5-HT 1A receptor antagonist WAY 100,635 and the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Pretreatment with WAY 100,635 blocked the 8-OH-DPAT-induced reduction in escape failures, but did not counteract the antidepressant effect of fluoxetine and paroxetine. PCPA given alone did not modify helpless behaviour nor did it affect the behavioural effect of 8-OH-DPAT, fluoxetine and paroxetine. Adaptive changes in 5-HT 1A receptor function were studied by measuring 8-OH-DPAT-mediated hypothermia and lower lip retraction (LLR) in the animals 24 h after LH test session. Fluoxetine and paroxetine treatments caused a marked reduction in agonist-induced responses, an effect completely prevented by WAY 100,635 and PCPA. In conclusion, whereas direct agonist activity at postsynaptic 5-HT 1A receptors attenuated helpless behaviour, the antidepressant-like effect of SSRIs was found to be independent of their actions on either 5-HT 1A receptor function or extracellular 5-HT.

Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study

We examined the effect of the administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and paroxetine on the activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized adult male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular recording. A single injection of 2.5 mg/kg (i.p.) of fluoxetine significantly increased the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of either 1 mg/kg (i.p.) of paroxetine or 5 mg/kg of fluoxetine significantly increased the number of spontaneously active VTA DA neurons. The repeated administration (one injection per day for 21 days) of all of the SSRIs produced a significant increase in the number of spontaneously active VTA DA neurons. Overall, our results indicate that the systemic administration of SSRI alters the activity of midbrain DA neurons with differential effects on VTA compared with SNC DA neurons.

Treatment benefits of duloxetine in major depressive disorder as assessed by number needed to treat

The efficacy of an antidepressant typically is assessed by comparing it with placebo using a validated rating scale. This type of analysis, however, does not translate well to the clinical settings. For clinicians, a more meaningful measure is the number needed to treat (NNT). The objective of this analysis is to assess the efficacy of duloxetine in terms of NNT. Data were obtained from nine clinical trials designed to assess the efficacy and safety of duloxetine as a treatment for major depressive disorder. These studies examined 8-9 weeks of acute treatment with duloxetine. NNT estimates were determined for duloxetine, selective serotonin reuptake inhibitor comparators from six multi-dose studies, and for duloxetine in patients > or =65 years of age. The NNT was based on the Hamilton Depression Rating Scale (HAMD17) for response and remission, and improvements defined by the Clinical Global Impression (CGI) were estimated and compared. The NNT was favorable for both duloxetine and selective serotonin reuptake inhibitor compared with placebo. The patients receiving duloxetine had NNT for HAMD17 response of 6.0, remission 7-9, and CGI-defined improvement 6-7 by 8 weeks. The NNTs for selective serotonin reuptake inhibitors (fluoxetine or paroxetine, 20 mg/day) were around 7 for response, 11 for remission, and 8 for CGI-defined improvement. The NNTs in the elderly were similar. The NNT for several measures of efficacy including remission consistently demonstrated the treatment benefits of duloxetine as well as of fluoxetine and paroxetine compared with placebo.

Paroxetine for somatic pain associated with physical illness: a review.

The purpose of this article is to review the prevalence of somatic pain with and without depression or anxiety and the pharmacologic effects of the selective serotonin reuptake inhibitor paroxetine on pain in physical conditions with and without comorbid depression or anxiety. MEDLINE and PsychLIT/PsycINFO database. Keywords included depression, anxiety, pain, somatic, antidepressants, and paroxetine. Only English-language publications and abstracts were considered. More than 100 articles that reflected the prevalence of somatic pain in patients with physical illness with and without comorbid depression or anxiety and that evaluated the efficacy of antidepressants in this population were identified and reviewed. Nearly two thirds of patients with major depressive disorder suffer from a physical illness, and about one fifth of patients with chronic physical illness are depressed. Both of these comorbidities pose diagnostic and therapeutic challenges. Therapeutic effects of antidepressants on pain improvement in patients with chronic physical illnesses and comorbid depression/anxiety have been attributed to the antidepressant or anxiolytic properties of these drugs. However, tricyclic antidepressants have demonstrated analgesic properties in patients with physical illness both with and without depression. The review looks at evidence for the efficacy of the selective serotonin reuptake inhibitor paroxetine on pain in physical illness with and without depression and the mechanisms for the relief of pain and depression. The efficacy of paroxetine for depression and anxiety comorbid with physical illness looks promising. Studies also allude to evidence linking the analgesic properties of paroxetine with its serotonergic and noradrenergic activity. Large randomized controlled trials within specific antidepressant classes and also comparing dualaction antidepressants are warranted that could shed some light on the unique advantage of paroxetine over other antidepressants.

Effectiveness of paroxetine in the treatment of obsessive–compulsive disorders

Clomipramine ushered in a new age of pharmacotherapy for obsessive–compulsive disorders, and it also facilitated our understanding of the biological aspects of obsessive–compulsive disorder, focusing on the serotonergic systems. The introduction of selective serotonin reuptake inhibitors has led to great progress in the pharmacological study of obsessive–compulsive disorder based on the serotonin hypothesis. Currently, selective serotonin reuptake inhibitors are positioned as a first-line drug of obsessive–compulsive disorder pharmacotherapy in the various guidelines and algorithms. Among six different selective serotonin reuptake inhibitors (paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, escitalopram) that are available worldwide, paroxetine has the broadest treatment spectrum and promises great benefits not only for obsessive–compulsive disorder patients, but also for those with comorbid depression and/or various kinds of anxiety disorders. This paper presents several clinical trials of paroxetine carried out, and discusses and reviews the therapeutic strategies for obsessive–compulsive disorder.

Effect of antidepressant drugs on 6-OHDA-treated mice in the FST

There is growing evidence suggesting that dopamine could be indirectly involved in the appearance of behavioural effects of antidepressants. In this study, we induced a partial (over 70%) and non-reversible depletion of dopamine-containing neurons in mice by i.c.v. infusion of 6-OHDA. Then, we compared the antidepressant-like effect of drugs (citalopram, paroxetine, desipramine and imipramine) with or without dopamine depletion in the mice forced swimming test. Our results clearly show that lesion with 6-OHDA does not modify the response of mice to desipramine and imipramine, whereas dopamine depletion abolished the antidepressant-like effect of citalopram and paroxetine. It could then be suggested that antidepressant-like effect of selective serotonin reuptake inhibitors (paroxetine and citalopram) in the mice FST requires the activation of dopaminergic pathways to occur.

Antiplatelet Activity During Coadministration of the Selective Serotonin Reuptake Inhibitor Paroxetine and Aspirin in Male Smokers: A Randomized, Placebo‐Controlled, Double‐blind Trial

Depression is associated with an increased incidence of vascular events and develops after stroke and myocardial infarction. Beside potential clinical outcome benefits of selective serotonin reuptake inhibitors for vascular diseases, bleeding events were reported. We investigated whether paroxetine and aspirin synergistically inhibit platelet function. Paroxetine (20 mg/d) was administered over 18 days to 20 men in a randomized, placebo-controlled, crossover design. Aspirin (100 mg/d) was coadministered within the last 4 study days. Platelet function was assessed by the platelet function analyzer and by flow cytometry. Paroxetine prolonged epinephrine-dependent predictive index within 14 days (P<.02). Aspirin enhanced the predictive index (P<.004 vs baseline and P>.05 between periods). A trend toward decreased thrombin receptor-activating peptide-induced CD62P expression after paroxetine was further enhanced by aspirin treatment (P>.05 between periods). The combination of paroxetine and aspirin did not further inhibit platelet plug formation under high shear stress in male smokers.

Selective serotonin reuptake inhibitors in sewage influents and effluents from Tromsø, Norway

An analytical method for quantification of the selective serotonin reuptake inhibitors (SSRIs) citalopram, sertraline, paroxetine, fluoxetine and fluvoxamine in sewage influents and effluents from selected sewage treatment plants (STPs) has been developed and validated. This quantification method is based on solid phase extraction of 2.5 L samples, followed by liquid–liquid extraction for further sample clean up in order to minimize matrix effects during subsequent quantification. The samples were analysed on a high performance liquid chromatograph coupled to a triple quadrupole mass spectrometric detector using 0.1% ammonia in acetonitrile/water as mobile phase, with positive electrospray ionisation and multiple reaction monitoring for detection and quantification. 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-pyrrolidine (N-7084) was used as internal standard for quantification. The recovery rates of the SSRIs ranged between 54 and 84%, and the method limit of quantification (MLQ) was between 120 and 290 pg/L for the target compounds. Samples were collected in July 2005 from three different STPs and a pump station in Tromsø, Northern Norway. Two of the STPs serve the University hospital and its psychiatric department, respectively, in addition to domestic sewage. SSRIs were detected in all samples collected. The concentrations varied greatly from below the MLQ to several hundreds ng/L. Concentrations in influents were higher compared to filtered effluents, indicating that SSRIs adsorb to particulate matter, are degraded by microorganisms, or degraded in other ways during the filtration process. However, more samples should be analysed before general conclusions can be drawn.

Phencyclidine-Induced Cognitive Deficits in Mice are Improved by Subsequent Subchronic Administration of Fluvoxamine: Role of Sigma-1 Receptors

This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.