Paxil

Psychopharmacology (Berl). 2005 Apr 28
Paroxetine is effective in desensitizing 5-HT1A receptor function in adult offspring exposed prenatally to cocaine.
Chen Z, Tetzlaff J, Sripathirathan K, Carrasco GA, Shankaran M, Van De Kar LD, Muma NA, Battaglia G.
Department of Pharmacology and Center for Serotonin Disorders Research, Stritch School of Medicine, Loyola University of Chicago, 2160 South First Avenue, Maywood, IL, 60153, USA.

RATIONALE: Desensitization of postsynaptic 5-HT(1A) receptors may be responsible for the therapeutic effectiveness of serotonin selective uptake inhibitors (SSRIs). As prenatal cocaine exposure produces long-term deficits in 5-HT neurons in offspring, it may alter the ability of postsynaptic 5-HT(1A) receptors to be desensitized by chronic paroxetine. OBJECTIVES: The aim of the study is to determine (1) prenatal cocaine-induced changes in 5-HT(1A) receptor function and (2) the effectiveness of chronic treatment with paroxetine to produce 5-HT(1A) receptor desensitization in adult offspring exposed to cocaine in utero. METHODS: Pregnant rats received saline or (-)cocaine (15 mg/kg, s.c.) twice daily from gestational days 13 through 20. Adult male offspring from each of prenatal groups were treated with saline or paroxetine (10 mg/kg/day; i.p.) for 14 days. Eighteen hours post-treatment, rats were challenged with saline or the 5-HT(1A) receptor agonist (+)8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.04 or 0.2 mg/kg, s.c.). Plasma oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, renin and prolactin were determined. RESULTS: Prenatal cocaine exposure did not alter 5-HT(1A) receptor-mediated neuroendocrine responses. Paroxetine treatment desensitized 5-HT(1A) receptor-mediated increases in oxytocin, ACTH and corticosterone to a comparable extent in all offspring and reduced the E(max) for ACTH only in prenatal cocaine-exposed offspring. Cortical [(3)H]-8-OH-DPAT- or [(3)H]-WAY100635-labeled 5-HT(1A) receptors were unaltered by prenatal cocaine or subsequent paroxetine treatment. CONCLUSIONS: Postsynaptic 5-HT(1A) receptor function is unaltered by prenatal cocaine exposure and paroxetine can effectively desensitize 5-HT(1A) receptor function in adult cocaine-exposed offspring. These data suggest that paroxetine may be clinically effective in treating mood disorders in adults exposed in utero to cocaine.

J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jun 5;820(1):33-9. Epub 2005 Apr 11.
Simultaneous determination of fluoxetine, citalopram, paroxetine, venlafaxine in plasma by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI).
Juan H, Zhiling Z, Huande L.
Clinical Pharmaceutical Research Institute, Second Xiangya Hospital, Central South University, Changsha 410011, PR China.

Fluoxetine, citalopram, paroxetine and venlafaxine have been widely used in the treatment of depression. However, no study has been conducted to determine the four drugs simultaneously by high performance liquid chromatography-electrospray ionization mass spectrometry (HPLC-MS/ESI). OBJECTIVE:: To establish a new, rapid and sensitive HPLC-MS/ESI method for simultaneous determination and screening in human plasma of the four most commonly prescribed nontricyclic antidepressants: fluoxetine, citalopram, paroxetine and venlafaxine. METHODS:: The analytes in plasma were extracted by solid-phase-extraction column after samples had been alkalinized. The HPLC separation of the analytes was performed on a MACHEREY-NAGEL C(18) (250mmx4.6mm, 5mum, Germany) column, using water (formic acid 0.6 per thousand, ammonium acetate: 30mmol/l)-acetonitrile (35:65, v/v) as mobile phase, with a flow-rate of 0.85ml/min. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer and were detected in the selected ion recording (SIR) mode. RESULTS:: The calibration curves were linear in the 5.0-1000.0ng/ml range for all compounds, all of them with coefficients of determination above 0.9900. The average extraction recoveries for all the four analytes were above 73.2%. The methodology recoveries were higher than 95.0%. The limits of detection (LODs) were 0.5, 0.3, 0.3 and 0.1ng/ml for fluoxetine, citalopram, paroxetine and venlafaxine, respectively. The intra- and inter-day variation coefficients were less than 15.0%. CONCLUSION:: The method is accurate, sensitive and simple for routine therapeutic drug monitoring (TDM) as well as toxicologic screening, and for the study of the pharmacokinetics and metabolism of the four drugs.

Rev Bras Psiquiatr. 2005 Mar;27(1):18-24. Epub 2005 Apr 18.
The efficacy of antidepressants for generalized anxiety disorder: a systematic review and meta-analysis.
Schmitt R, Gazalle FK, Lima MS, Cunha A, Souza J, Kapczinski F.
University Hospital, Federal University, RS, Brazil.

OBJECTIVE: To investigate the efficacy and acceptability of antidepressants in the treatment of generalized anxiety disorder. METHODS: All randomized controlled trials assessing the use of antidepressants in generalized anxiety disorder up to may 2002 were included. Non randomized trials and those that included patients with both generalized anxiety disorder and another Axis I co-morbidity were excluded. Relative risks, weighted mean difference and number needed to treat were estimated. People who died or dropped out were regarded as having had no improvement. RESULTS: Antidepressants (imipramine, venlafaxine and paroxetine) were found to be superior to placebo in treating generalized anxiety disorder. The calculated number needed to treat for antidepressants in generalized anxiety disorder was 5.15. Dropout rates did not differ between antidepressants and placebo. CONCLUSION: The available evidence suggests that antidepressants would probably be a reasonable treatment for generalized anxiety disorder patients in the clinical context.

Breast Cancer Res Treat. 2005 Feb;89(3):243-9.
Effect of paroxetine hydrochloride (Paxil((R))) on fatigue and depression in breast cancer patients receiving chemotherapy.
Roscoe JA, Morrow GR, Hickok JT, Mustian KM, Griggs JJ, Matteson SE, Bushunow P, Qazi R, Smith B.
University of Rochester Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, New York, 14642, USA, Joseph_Roscoe@urmc.rochester.edu.
Background. Fatigue can significantly interfere with a cancer patient's ability to fulfill daily responsibilities and enjoy life. It commonly co-exists with depression in patients undergoing chemotherapy, suggesting that administration of an antidepressant that alleviates symptoms of depression could also reduce fatigue.Methods. We report on a double-blind clinical trial of 94 female breast cancer patients receiving at least four cycles of chemotherapy randomly assigned to receive either 20 mg of the selective serotonin re-uptake inhibitor (SSRI) paroxetine (Paxil(R), SmithKline Beecham Pharmaceuticals) or an identical-appearing placebo. Patients began their study medication seven days following their first on-study treatment and continued until seven days following their fourth on-study treatment. Seven days after each treatment, participants completed questionnaires measuring fatigue (Multidimensional Assessment of Fatigue, Profile of Mood States-Fatigue/Inertia subscale and Fatigue Symptom Checklist) and depression (Profile of Mood States-Depression subscale [POMS-DD] and Center for Epidemiologic Studies-Depression [CES-D]).Results. Repeated-measures ANOVAs, after controlling for baseline measures, showed that paroxetine was more effective than placebo in reducing depression during chemotherapy as measured by the CES-D (p=0.006) and the POMS-DD (p=0.07) but not in reducing fatigue (all measures, ps > 0.27).Conclusions. Although depression was significantly reduced in the 44 patients receiving paroxetine compared to the 50 patients receiving placebo, indicating that a biologically active dose was used, no significant differences between groups on any of the measures of fatigued were observed. Results suggest that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment.

Addiction. 2005 Mar;100 Suppl 1:12-22.
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.

Consum Rep. 2004 Oct;69(10):22-9.
Drugs vs. talk therapy: 3,079 readers rate their care for depression and anxiety.
With or without drugs, most people who sought care for depression or anxiety gained relief. A survey of thousands of CR subscribers who recently received treatment for those conditions found that: (1) a combination of talk therapy and drugs often worked best. But "mostly talk" therapy was almost as effective if it lasted for 13 or more visits. (2) "Mostly drug" therapy was also effective for many people. Drugs had a quicker impact on symptoms than talk therapy, but it often took trial and error to find a drug that worked without unacceptable side effects. (3) Forty percent of people who took antidepressants complained of adverse sexual side effects. (4) Care from primary-care doctors was effective for people with mild problems, but less so for people with severe ones.

Environ Toxicol Chem. 2004 Sep;23(9):2229-33.
Acute and chronic toxicity of five selective serotonin reuptake inhibitors in Ceriodaphnia dubia.
Henry TB, Kwon JW, Armbrust KL, Black MC.
Department of Environmental Health Science, University of Georgia, Athens, Georgia 30602, USA. thenry@uga.edu
Contamination of surface waters by pharmaceutical chemicals has raised concern among environmental scientists because of the potential for negative effects on aquatic organisms. Of particular importance are pharmaceutical compounds that affect the nervous or endocrine systems because effects on aquatic organisms are possible at low environmental concentrations. Selective serotonin reuptake inhibitors (SSRIs) are drugs used to treat clinical depression in humans, and have been detected in low concentrations in surface waters. In this investigation, the acute and chronic toxicity of five SSRIs (fluoxetine, Prozac; fluvoxamine, Luvox; paroxetine, Paxil; citalopram, Celexa; and sertraline, Zoloft) were evaluated in the daphnid Ceriodaphnia dubia. For each SSRI, the 48-h median lethal concentration (LC50) was determined in three static tests with neonate C. dubia, and chronic (8-d) tests were conducted to determine no-observable-effect concentrations (NOEC) and lowest-observable-effect concentrations (LOEC) for reproduction endpoints. The 48-h LC50 for the SSRIs ranged from 0.12 to 3.90 mg/L and the order of toxicity of the compounds was (lowest to highest): Citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline. Mortality data for the 8-d chronic tests were similar to the 48-h acute data. The SSRIs negatively affected C. dubia reproduction by reducing the number of neonates per female, and for some SSRIs, by reducing the number of broods per female. For sertraline, the most toxic SSRI, the LOEC for the number of neonates per female was 0.045 mg/L and the NOEC was 0.009 mg/L. Results indicate that SSRIs can impact survival and reproduction of C. dubia; however, only at concentrations that are considerably higher than those expected in the environment.

JAMA. 2004 Jul 21;292(3):338-43.
Antidepressants and the risk of suicidal behaviors.
Antidepressants and the risk of suicidal behaviors.
Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, Mass 02421, USA. hjick@bu.edu
CONTEXT: The relation between use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. OBJECTIVE: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with 1 of 3 antidepressant drugs compared with patients starting treatment with dothiepin. DESIGN AND SETTING: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993-1999. PARTICIPANTS: The base population included 159,810 users of the 4 antidepressant drugs. Participants could have used only 1 of these antidepressants and had to have received at least 1 prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). MAIN OUTCOME MEASURES: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. RESULTS: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the 4 study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38.0 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. CONCLUSIONS: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the 4 drugs on people aged 10 to 19 years.

Ann Pharmacother. 2004 Jul-Aug;38(7-8):1197-201. Epub 2004 May 18.
SSRI treatment-associated stroke: causality assessment in two cases.
Ramasubbu R.
Department of Psychiatry, University of Calgary, Foothills Medical Centre, Rm. AW258A, 1403 29th St NW, Calgary, Alberta T2N 2T9, Canada. rramasub@ucalgary.ca
OBJECTIVE: To assess the probability of cerebrovascular adverse drug reactions (CV-ADRs) due to treatment with selective serotonin-reuptake inhibitors (SSRIs) using 2 causality methods. case summaries: Two patients with the possibility of SSRI-related stroke were referred for causality assessment. Causality assessment was performed using an adverse drug reaction probability scale, as well as clinical and radiologic parameters. A 31-year-old white man, who had been receiving paroxetine 200 mg/day over a period of 3 years, developed ischemic stroke involving left middle cerebral artery. The second patient was a 46-year-old white woman with a history of recurrent depression who developed delirium and ischemic stroke while she was taking a combination of paroxetine 50 mg/day, trazodone 200 mg/day, and bupropion 150 mg/day. DISCUSSION: Carotid and cardiothromboembolism were found to be the major etiological factors for ischemic stroke. Accounting for the temporal relation, prior reports of SSRI treatment-associated CV-ADRs, and the pharmacologic action of serotonin on coagulation and the vascular system, the possible contribution of SSRIs to stroke in these patients was considered. An objective causality assessment using the Naranjo probability scale revealed that a CV-ADR was possible. However, the nature of the stroke, plus clinical and radiologic findings, were inconsistent with known pathophysiologic mechanisms linking SSRIs and stroke in these patients. CONCLUSIONS: Causality assessment may improve unbiased recognition, management, and voluntary reporting of infrequent adverse effects such as SSRI treatment-related cerebrovascular accident.

J Clin Psychiatry. 2004 Jul;65(7):915-8.
Paroxetine, other antidepressants, and youth suicide in New York City: 1993 through 1998.
Leon AC, Marzuk PM, Tardiff K, Teres JJ.
Department of Psychiatry, Weill Medical College of Cornell University, New York, NY10021, USA. acleon@med.cornell.edu
BACKGROUND: Regulatory agencies in the United Kingdom and the United States have recently issued warnings about a possible link between suicidal ideation and attempts and the use of paroxetine in a pediatric patient population. The objective of this study was to determine the proportion of youth suicides that tested positive for paroxetine or other antidepressants in medical examiner toxicologic testing in New York City from 1993 through 1998, the first 6 years that paroxetine was available in the United States. METHOD: Subjects in this medical examiner surveillance study were suicides less than 18 years of age. Serum toxicology was examined for paroxetine and other antidepressants. RESULTS: There were 66 suicides among persons under 18 years of age in the years 1993 through 1998. Toxicology was tested in 58 (87.9%) of the 66 suicides, and 54 (81.8%) had injury-death intervals of 3 days or less. None of the victims had paroxetine detected in their blood obtained at the time of autopsy. Imipramine was detected in 2 victims and fluoxetine in another 2. CONCLUSION: Despite regulatory concerns, none of the autopsies of youth suicides in New York City detected paroxetine in the victims, although other antidepressants were detected in 4 victims. However, in the vast majority of the youth suicides, there was no evidence of anti-depressant use immediately prior to death.

J Pharmacol Exp Ther. 2004 Jul;310(1):141-9. Epub 2004 Mar 19.
Mechanisms for the inhibition of genital vascular responses by antidepressants in a female rabbit model.
Angulo J, Cuevas P, Cuevas B, Gupta S, Saenz de Tejada I.
Fundacion para la Investigacion y el Desarrollo en Andrologia, Madrid, Spain.
Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to pelvic nerve electrical stimulation in female rabbits were measured by laser Doppler flow needle probes. The intravenous administration of various treatments was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5 and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine-induced reduction of GVRs but had no effect on the inhibition of GVRs induced by venlafaxine. Conversely, the alpha-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of alpha-adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.

J Psychiatr Res. 2004 Jul-Aug;38(4):365-70.
The association between panic disorder and the L/L genotype of catechol-O-methyltransferase.
Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH.
Department of Neuropsychiatry, Inje University Seoul Paik Hospital, Seoul, Republic of Korea.
To clarify the role of catechol-O-methyltransferase (COMT) polymorphism in panic disorder (PD), we investigated a large group of Korean PD patients (N = 178) and controls (N = 182) using a case-control study. We also assessed the response to paroxetine treatment and other clinical variables in the PD patients. The increase in the COMT(L) allele was not statistically significant in PD (p = 0.104). However, compared with the sum of the other genotypes, the frequency of the L/L genotype was significantly higher in PD (p = 0.042). The odd ratios (ORs) also indicated a significant effect of the homozygosity for the COMT(L) allele on an increased risk for PD (OR=2.38; 95% CI 1.03-5.51). In addition, patients with L/L genotype had higher trait-anxiety levels (p = 0.030) and poorer treatment response to paroxetine than those with other genotypes (p = 0.002). Our results suggest that the COMT L/L genotype is associated with PD and the genetic variant of the COMT enzyme may be related to the clinical severity and treatment response to paroxetine in PD.

Psychoneuroendocrinology. 2004 Jul;29(6):757-66.
Influence of menstrual cycle on platelet serotonin uptake site and serotonin2A receptor binding.
Wihlback AC, Sundstrom Poromaa I, Bixo M, Allard P, Mjorndal T, Spigset O.
Department of Clinical Sciences/Obstetrics and Gynecology, University Hospital of Umea, S-901 85 Umea, Sweden. anna-carin.wihlback@obgyn.umu.se
Depression and anxiety are common health problems affecting women, particularly during the reproductive years. Major depression is two to three times as common in women than in men. Neuroendocrine factors are likely to contribute to this overall increased risk for developing mood disorders in women, and the neuroendocrine influence is most obviously seen in women with premenstrual dysphoric disorder (PMDD) as these women experience depressed mood and anxiety premenstrually only during ovulatory cycles. Moreover, dysfunction of serotonergic transmission has been regarded as an important mechanism in several psychiatric disorders and ovarian steroids have been shown to profoundly influence the activity of the serotonergic system. Given these facts, the purpose of this study was to examine whether binding of [3H]paroxetine to the platelet serotonin transporter or binding of [3H]lysergic acid diethylamide ([3H]LSD) to the platelet 5-HT2A receptor are influenced by the cyclical changes in circulating estradiol and progesterone that occur during the menstrual cycle. We examined 28 healthy women, without oral contraceptives and with regular menstrual cycles. In the late follicular phase, Bmax for [3H]paroxetine binding was significantly higher than in the ovulatory (p<0.01), early luteal phase (p<0.05) and mid-luteal phase (p<0.01). Bmax for [3H]LSD binding was significantly higher in the early follicular phase and the early luteal phase compared to the mid-luteal phase (p<0.001 and p<0.05, respectively). In the early follicular phase and the ovulatory phase, significant correlations between estradiol serum concentrations and Kd for [3H]paroxetine were obtained (p<0.001, respectively). In the luteal phase, significant inverse correlations between progesterone as well as estradiol serum concentrations and Kd for [3H]LSD binding were found (p<0.05, respectively).

Psychoneuroendocrinology. 2004 Jul;29(6):733-40.
Heart rate variability in premenstrual dysphoric disorder.
Landen M, Wennerblom B, Tygesen H, Modigh K, Sorvik K, Ysander C, Ekman A, Nissbrandt H, Olsson M, Eriksson E.
Section of Psychiatry, Institute of Clinical Neuroscience, Goteborg University, Gothenburg, Sweden. landenm@msx.upmc.edu
Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.

Brain Res Dev Brain Res. 2004 Jun 21;150(2):151-61.
Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development.
Xu Y, Sari Y, Zhou FC.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
To further investigate the role of the transiently expressed serotonin (5-HT) transporter (5-HTT) in the development of thalamic fibers projecting to cortical barrels and the potential developmental changes in neuronal circuitry caused by a selective serotonin reuptake inhibitor (SSRI), paroxetine (5 mg/kg, twice daily, s.c.) or saline was administered to rat pups from postnatal day 0 (P0) to P8. Pups were perfused on P8 for 5-HT immunostaining (-im) to confirm the 5-HT uptake blockade, and 5-HTT-im and phospholipase C-beta1 (PLC-beta1)-im to label the thalamic afferents to barrels and barrel cells respectively. Paroxetine treatment completely blocked 5-HT uptake into the thalamocortical fibers as indicated by the negative 5-HT-im in cortical barrel areas. Organization of thalamic afferents to barrels, indicated by 5-HTT-im or PLC-beta1, was altered in paroxetine-treated pups in the following manners: (1) segregation of thalamocortical fibers was partially disrupted and thalamocortical fibers corresponding to anterior snouts and row A mystacial vibrissae were fused; (2) sizes of the unfused thalamocortical fiber patches related to the long caudal vibrissae in rows B, C, D and E were significantly decreased without changes in the brain weights and cortical areas representing these vibrissae; and (3) thalamocortical fibers corresponding to C4 and D4 vibrissae tended to be closer to each other along the arc while the relative positions of thalamocortical fibers related to the rest of the vibrissae were normal. Our study demonstrated that 5-HTT plays an important role in the refinement, but not the formation, of barrel-like clusters of thalamocortical fibers and that the development of neural circuitry in rodent somatosensory cortex was affected by exposure to a SSRI during thalamocortical synaptic formation.

Environ Sci Technol. 2004 Jun 15;38(12):3351-9.
Environmental risk assessment of paroxetine.
Cunningham VL, Constable DJ, Hannah RE.
Corporate Environment, Health and Safety, GlaxoSmithKline, 2200 Renaissance Boulevard, Suite 105, King of Prussia, Pennsylvania 19406, USA. virginia.l.cunningham@gsk.com
Paroxetine hydrochloride hemihydrate (the active ingredient in Paxil) is a pharmaceutical compound used for the treatment of depression, social anxiety disorder, obsessive compulsive disorder, panic disorder, and generalized anxiety disorder. Paroxetine (PA) is extensively metabolized in humans, with about 97% of the parent compound being excreted as metabolites through the urine and feces of patients. Therefore PA and metabolites have the potential to be discharged into wastewater treatment systems after therapeutic use. PA and its major human metabolite (PM) were investigated using studies designed to describe physical/chemical characteristics and determine their fate and effects in the aquatic environment. A significant portion of the PM entering a wastewater treatment plant would be expected to biodegrade given the higher activated sludge solids concentrations present in a typical wastewater treatment plant. The potential for direct photolysis of PM is also possible based on photolysis results for PA itself. These results provide strong support for expecting that PA and PM residuals will not persist in the aquatic environment after discharge from a wastewater treatment facility. This conclusion is also supported by the results of a USGS monitoring study, where no PM was detected in any of the samples at the 260 ng/L reporting limit. The results presented here also demonstrate the importance of understanding the human metabolism of a pharmaceutical so that the appropriate molecule(s) is used for fate and effects studies. In addition to the PA fate studies, PM was investigated using studies designed to determine potential environmental effects and a predicted no effect level (PNEC). The average measured activated sludge respiration inhibition value (EC50) for PM was 82 mg/L. The measured Microtox EC50 value was 33.0 mg/L, while the Daphnia magna EC50 value was 35.0 mg/L. The PNEC for PM was calculated to be 35.0 microg/L. Fate data were then used in a new watershed-based environmental risk assessment model, PhATE, to predict environmental concentrations (PECs). Comparison of the calculated PECs with the PNEC allows an assessment of potential environmental risk. Within the 1-99% of stream segments in the PhATE model, PEC values ranged from 0.003 to 100 ng/L. The risk assessment PEC/PNEC ratios ranged from approximately 3 x 10(-8) to approximately 3 x 10(-3), indicating a wide margin of safety, since a PEC/PNEC ratio <1 is generally considered to represent a low risk to the environment. In addition, Microtox studies carried out on PM biodegradation byproducts indicated no detectable residual toxicity. Any compounds in the environment as a result of the biodegradation of PM should be innocuous polar byproducts that should not exert any toxic effects.

Environ Toxicol Chem. 2004 Jun;23(6):1394-9.
Hydrolysis and photolysis of paroxetine, a selective serotonin reuptake inhibitor, in aqueous solutions.
Kwon JW, Armbrust KL.
Mississippi State Chemical Laboratory, Mississippi State University, PO Box CR, Mississippi State, Mississippi 39762, USA.
The hydrolysis and photolysis of paroxetine HCI, a selective serotonin reuptake inhibitor, in aqueous buffer solutions (pH 5, 7, and 9), in synthetic humic water, and in lake water were investigated at 25 degrees C in the dark and in a growth chamber outfitted with fluorescent lamps simulating the ultraviolet (UV) output of sunlight. Paroxetine was degraded completely within 4 d by simulated sunlight in all aqueous media. Photolysis of paroxetine HCI was accelerated by increasing pH. The t1/2 values at pH 5, 7, and 9 were 15.79, 13.11, and 11.35 h, respectively. The half-lives of paroxetine in synthetic humic water and two lake waters were slightly longer than in pH 7 buffer. Two photoproducts were detected and their structures were identified by liquid chromatography-mass spectrometry in positive mode. Photoproduct I was found to be photolytically unstable, being gradually degraded after 12 to 18 h of irradiation. However, photoproduct II was photolytically very stable throughout the experiment period, indicating that it was persistent to further photodegradation. In the dark, paroxetine in all aqueous solutions was found to be stable over a 30-d period. In conclusion, paroxetine is a relatively photolabile drug that has a possibility of photodegradation by sunlight in surface water.

Biol Psychiatry. 2003 Oct 1;54(7):693-702.
Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder.
Vermetten E, Vythilingam M, Southwick SM, Charney DS, Bremner JD.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.
BACKGROUND: Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. METHODS: Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. RESULTS: Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. CONCLUSIONS: These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.