paroxetine, Paxil
Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers.

Begre S, von Bardeleben U, Ladewig D, Jaquet-Rochat S, Cosendai-Savary L, Golay KP, Kosel M, Baumann P, Eap CB.

Psychiatrische Universitatsklinik Basel, Basel, Switzerland.

Steady-state blood concentrations of (R)- methadone (i.e., the active form), (S)-methadone, and (R,S)-methadone were measured before and after introduction of paroxetine 20 mg/day during a mean period of 12 days in 10 addict patients in methadone maintenance treatment. Eight patients were genotyped as CYP2D6 homozygous extensive metabolizers (EMs) and two patients as poor metabolizers (PMs). Paroxetine significantly increased concentrations of both enantiomers of methadone in the whole group (mean increase for (R)-methadone +/- SD, 26 +/- 32%; range, -14% to +83%, p = 0.032; for (S)-methadone, 49 +/- 51%; range, -29% to +137%, p = 0.028; for (R,S)-methadone, 35 +/- 41%; range, -20% to +112%, p = 0.032) and in the group of eight EMs (mean increase, 32%, p = 0.036; 53%, p = 0.028; and 42%, p = 0.036, for (R)-methadone, (S)-methadone, and (R,S)-methadone, respectively). On the other hand, in the two PMs, (S)-methadone but not (R)-methadone concentrations were increased by paroxetine (mean increases of 36% and 3%, respectively). Paroxetine is a strong CYP2D6 inhibitor, and these results confirm previous studies showing an involvement of CYP2D6 in methadone metabolism with a stereoselectivity toward the (R)-enantiomer. Because paroxetine is a mild inhibitor of CYP1A2, CYP2C9, CYP2C19, and CYP3A4, increase of (S)-methadone concentrations in both EMs and PMs could be mediated by inhibition of any of these isozymes.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11910269&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Somatodendritic action of pindolol to attenuate the paroxetine-induced decrease in serotonin release from the rat ventral hippocampus: a microdialysis study.

Miguez JM, Paz-Valinas L, Miguez I, Aldegunde M.

Laboratory Fisioloxia Animal, Departamento Bioloxia Funcional e Ciencias da Saude, Facultade de Ciencias, Universidade de Vigo, 36200 Vigo, Spain. jmmiguez uvigo.es

We used intracerebral microdialysis to study the role of raphe and presynaptic serotonin (5-HT) autoreceptors in the effect of the selective 5-HT reuptake inhibitor, paroxetine, on 5-HT release from ventral hippocampus of anaesthetised rats. In addition, we have tested the ability of pindolol, a non-selective beta-adrenergic/5-HT(1A) receptor antagonist, to alter the response of hippocampal 5-HT to paroxetine. Doses of paroxetine with maximal effects were near to three-fold less effective when administered systemically than after local infusion at increasing extracellular 5-HT in ventral hippocampus. Moreover, systemic paroxetine treatment resulted in a marked decrease of the extracellular 5-HT in the hippocampus when 5-HT reuptake was blocked with paroxetine 3 microM applied locally, thereby evidencing that systemic treatment induced a decrease of 5-HT release in the neuronal terminal. A similar drop was observed when paroxetine 3 microM was perfused into the median raphe, a region that contains the cell bodies of the neurons innervating the ventral hippocampus. Racemic (+/-)-pindolol (10 mg/kg, s.c.) completely blocked the paroxetine-induced decrease in 5-HT release from rat hippocampus. In addition, the infusion into median raphe of (-)-pindolol, the isoform with highest antagonist activity, at concentrations of 10 microM and 100 microM was able to partially block the decrease of hippocampal 5-HT release after systemic paroxetine. However, perfusion of (-)-pindolol into the hippocampus was without effect on local 5-HT release. These data suggest that pindolol acts preferentially through the blockade of somatodendritic 5-HT(1A) autoreceptors to restore the decline in 5-HT outflow in rat forebrain following systemic administration of selective 5-HT reuptake inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12012024&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C.

Kraus MR, Schafer A, Faller H, Csef H, Scheurlen M.

Medizinische Poliklinik, University of Wurzburg, Klinikstrasse 6-8, D-97070 Wurzburg, Germany. m.kraus mail.uni-wuerzburg.de

BACKGROUND: Psychiatric side-effects may require dose reduction or premature discontinuation of interferon therapy in chronic hepatitis C. New strategies are needed in order to prevent the premature termination of interferon therapy. AIM: To evaluate prospectively the efficacy and tolerability of antidepressant therapy (paroxetine, a selective serotonin reuptake inhibitor) in patients with chronic hepatitis C treated with interferon-alpha who have developed interferon-induced major depression. METHODS: A sub-group of 14 individuals from 121 consecutively treated hepatitis C patients developed substance-induced major depression without suicidal ideation during interferon-alpha treatment. The individuals in this sub-group received paroxetine after the occurrence of depression (20 mg daily until termination of interferon therapy). Diagnostic scores for depression (and anger-hostility) were obtained in a repeated measures design (Hospital Anxiety and Depression Scale and Symptom Checklist 90 Items Revised). RESULTS: Eleven of the 14 patients (78.6%) with interferon-induced major depression were able to complete interferon-alpha therapy as scheduled under concomitant paroxetine treatment (three dropouts: insufficient improvement of depression, occurrence of epileptic seizures, paroxetine-induced nausea/dizziness). Within 4 weeks after the start of paroxetine medication, depression scores declined significantly in all patients. CONCLUSIONS: Our data suggest that concomitant therapy with paroxetine is an effective way to treat interferon-induced depression in patients with chronic hepatitis C.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12030950&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Acute effects of amperozide and paroxetine on social cohesion in male conspecifics.

Rademacher DJ, Anderson AP, Steinpreis RE.

Department of Psychology, University of Wisconsin--Milwaukee, Milwaukee, WI, USA. drademac mcw.edu

The effects of acute administration of the selective 5-hydroxytrypamine (5-HT; serotonin) uptake inhibitor, paroxetine, and the potent 5-HT(2A) receptor antagonist, N-ethyl-4-[4',4'-bis(rho-flourophenyl)butyl]-1-piperazinecarboxamide (amperozide) on social cohesion was determined by using a tether paradigm, in which the movement of one of a pair of rats was restricted to one-half of an observation chamber. Administration of 0.1mg/kg paroxetine, 1.0, 3.0, and 5.0mg/kg amperozide but neither 1.0 nor 10.0mg/kg paroxetine increased time spent in contact with the untreated, tethered rat. Whereas only the lowest dose of paroxetine (0.1mg/kg) promoted social cohesion, all doses of amperozide (1.0, 3.0, and 5.0mg/kg) promoted social cohesion. The amperozide-induced increases in time spent in contact were greater than the paroxetine-induced increases in seconds spent in contact, regardless of dose. Acute administration of amperozide is more effective than acute administration of paroxetine in promoting social cohesion between pairs of male conspecifics. Amperozide may be an effective alternative treatment for patients with social anxiety disorder suffering from adverse side effects of paroxetine. Amperozide may prove to be a more effective treatment for social anxiety disorder than paroxetine, which is supported by our results.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12127016&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of chronic treatment with milnacipran on sleep architecture in rats compared with paroxetine and imipramine.

Gervasoni D, Panconi E, Henninot V, Boissard R, Barbagli B, Fort P, Luppi PH.

INSERM U480, Neurobiologie des etats de sommeil et d'eveil, 8 Avenue Rockefeller, 69373 Lyon, France.

A number of studies in humans and various other species have shown that chronic treatment with antidepressants, such as tricyclics or selective serotonin reuptake inhibitors (SSRIs), induces a decrease or suppression of rapid eye movement (REM) sleep. The effect of a new selective serotonin and noradrenaline reuptake inhibiting (SNRI) antidepressant, milnacipran, on REM sleep has been investigated and compared with that of the SSRI, paroxetine, and the tricyclic, imipramine. Rats injected with vehicle or milnacipran twice a day showed, over 24 h, a similar amount of REM sleep, number and duration of REM sleep episodes to control rats. In contrast, rats treated acutely with imipramine or paroxetine showed a statistically significant decrease in the total quantity of REM sleep. The number of REM sleep episodes was decreased while their duration was increased. A more detailed analysis showed further that the quantity of REM sleep was decreased for the first 4 h following the 9 a.m. injection but not the 7 p.m. injection for milnacipran, during the first 6 h for paroxetine and for the entire light-dark period for imipramine. For all drugs, the quantities of slow-wave sleep and waking over 24 h were not significantly different from control conditions and no rebound of REM sleep occurred during the day following withdrawal. Power spectrum analysis revealed no global changes in the different electroencephalogram (EEG) waves (delta, theta, gamma) between the control condition and the different treatments during waking, slow-wave sleep or REM sleep. Taken together our results indicate that the SNRI, milnacipran, at therapeutic doses, induces only minor disturbances of REM sleep compared with a SSRI and tricyclic antidepressant used. Possible mechanisms responsible for the difference of action on REM sleep of milnacipran are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12151030&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine treatment of mood and anxiety disorders in children and adolescents.

Wagner KD.

Department of Psychiatry, University of Texas Medical Branch, TX 77555-0188, USA. Kwagner utmb.edu

This article provides an overview of the use of paroxetine in the treatment of mood and anxiety disorders in children and adolescents. Although not currently approved for use in patients younger than 18 years of age, the efficacy and safety of paroxetine have been studied in several pediatric mood and anxiety disorders. The epidemiology, diagnosis, and course of major depression, obsessive-compulsive disorder, social anxiety disorder, and panic disorder are discussed briefly. Current available data on the safety and efficacy of paroxetine based on double-blind, placebo-controlled trials and open-label studies for the treatment of mood and anxiety disorders in children and adolescents are reviewed. Clinical guidelines for the use of paroxetine in children and adolescents and recommendations regarding future directions of study are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14566209&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Influences of the corticotropic axis and sympathetic activity on neurochemical consequences of 3,4-methylenedioxymethamphetamine (MDMA) administration in Fischer 344 rats.

Fernandez F, Aguerre S, Mormede P, Chaouloff F.

NeuroGenetique et Stress, INSERM U471-INRA, Institut F. Magendie, Rue Camille Saint Saens, 33077 Bordeaux Cedex, France.

The respective influences of the corticotropic axis and sympathetic activity on 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) immediate effects on body temperature and long-term neurotoxicity, as assessed by decreases in hippocampal and striatal [(3)H]5-hydroxytryptamine ([(3)H]5-HT) reuptake, [(3)H]paroxetine binding at 5-HT transporters (5-HTT), and 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels, were examined in Fischer 344 rats. On each of the two injections of MDMA (5 or 10 mg/kg s.c. once a day for 2 consecutive days) body temperature rapidly increased in a dose-dependent manner. Six days after the last injection of 10 mg/kg MDMA, [(3)H]5-HT reuptake, [(3)H]paroxetine binding and 5-HT and 5-HIAA levels were decreased in the hippocampus and, to a lower extent, in striatum. Prior adrenalectomy (1 week beforehand), which weakened the immediate hyperthermic effect of MDMA, prevented the long-term MDMA-elicited reduction in hippocampal and striatal [(3)H]paroxetine binding. Supplementation of adrenalectomised Fischer 344 rats with corticosterone almost reinstated the immediate hyperthermic effect of MDMA and restored MDMA-elicited reduction in hippocampal and striatal [(3)H]paroxetine binding. In a final set of experiments, Fischer 344 rats were pretreated (30 min before each of the two injections of 10 mg/kg MDMA) with the ganglionic blocker chlorisondamine (2.5 mg/kg). This pretreatment markedly reduced the amplitudes of the immediate hyperthermia and long-term declines in hippocampal [(3)H]5-HT reuptake and [(3)H]paroxetine binding at 5-HTT, and in hippocampal and striatal 5-HT and 5-HIAA levels. These results suggest that sympathetic activity (possibly through its control of body temperature), but not corticotropic activity, plays a key role in MDMA-elicited neurotoxicity in Fischer 344 rats.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12270036&dopt=Abstract paroxetine, Paxil, Paxil CR