paroxetine, Paxil
Intracerebroventricular infusion of leptin decreases serotonin transporter binding sites in the frontal cortex of the rat.

Charnay Y, Cusin I, Vallet PG, Muzzin P, Rohner-Jeanrenaud F, Bouras C.

Division de Neuropsychiatrie, Belle-Idee, H.U.G, Ch. du Petit-Bel-Air 2, CH-1225 Chene-, Bourg, Switzerland. charnay uni2a.nige.ch

We demonstrate that chronic intracerebroventricular infusion of leptin dramatically decreases the number of [(3)H]paroxetine binding sites in the frontal cortex of the rat brain. In contrast, the density in paroxetine binding sites estimated in the region containing raphe projecting cell bodies (i.e., the dorsal and median raphe nuclei) remains unchanged. Since leptin treatment significantly decreases food intake, [(3)H]paroxetine binding parameters were also estimated in the frontal cortex of pair-fed control rats. No significant difference in [(3)H]paroxetine binding was observed between pair-fed and ad libitum fed control rats. These data indicate that leptin treatment could regionally down-regulate serotonin transporter binding sites in the brain. Although the cellular and molecular mechanisms underlying such an effect of leptin need further investigation, our observations support the notion of a possible interaction between leptin and the serotonergic system of potential interest in the pathophysiology of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10739882&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Improved synthesis of paroxetine hydrochloride propan-2-ol solvate through one of metabolites in humans, and characterization of the solvate crystals.

Sugi K, Itaya N, Katsura T, Igi M, Yamazaki S, Ishibashi T, Yamaoka T, Kawada Y, Tagami Y, Otsuki M, Ohshima T.

Central Research Laboratories, Sumika Fine Chemicals Co., Ltd., Osaka, Japan.

Paroxetine, a potent and selective inhibitor of 5-hydroxytryptamine (serotonin) uptake, was prepared through a piperidine derivative, which was reported to be one of the paroxetine metabolites in humans. Thus, the piperidine derivative was converted to its N-tert-butoxycarbonyl (N-Boc) derivative, which was then converted to N-Boc paroxetine. Paroxetine hydrochloride propan-2-ol (isopropyl alcohol (IPA)) solvate crystals were directly obtained from the N-Boc paroxetine by adding hydrogen chloride to the N-Boc paroxetine IPA solution. The amount of IPA content in the crystals was reduced by drying with a continuous change of powder X-ray diffraction patterns. Other characterizations of the solvate crystals were also conducted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10783073&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine binding in aggressive schizophrenic patients.

Modai I, Gibel A, Rauchverger B, Ritsner M, Klein E, Ben-Shachar D.

Sha'ar Menashe Mental Health Center and Institute of Psychiatric Studies, Hadera, Israel. shrmodai matat.health.gov.il

Decreased central serotonergic activity has been associated with aggressive behavior in humans and animals. Whether or not this phenomenon is related to current aggression or to aggressive tendency is debatable. [3H]paroxetine binding in blood platelets represents the activity of serotonin peripheral binding sites. We investigated a possible association between [3H]paroxetine binding in blood platelets and current aggression or homicidal history in schizophrenic patients. Blood platelets of 11 aggressive schizophrenic patients were assayed for [3H]paroxetine binding in blood platelets and compared to findings in 15 non-aggressive schizophrenic patients, 15 presently non-aggressive schizophrenic patients with homicidal history, and 15 healthy volunteers. Clinical evaluation was performed using the Positive and Negative Syndrome Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scale. B(max) of [3H]paroxetine binding in blood platelets of currently aggressive schizophrenic patients was significantly higher than that in platelets of non-aggressive schizophrenic patients, presently non-aggressive patients with homicidal history and healthy volunteers. No difference was found between the last three study groups. No significant correlation was found between scores of all rating scales and the investigated biochemical parameters. An association was found between current aggression among schizophrenic patients and high B(max) values of [3H]paroxetine binding in blood platelets. This association is probably related to present state of aggression rather than to tendency towards aggression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10788680&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effects of the co-administration of mirtazapine and paroxetine on serotonergic neurotransmission in the rat brain.

Besson A, Haddjeri N, Blier P, de Montigny C.

Neurobiological Psychiatry Unit, McGill University, 1033 Pine Avenue, West Montreal, Quebec, Canada.

The alpha(2)-adrenoreceptor antagonist mirtazapine, which is also a 5-HT(2), 5-HT(3) and H(1) receptors antagonist and the selective serotonin (5-HT) reuptake inhibitor paroxetine are effective antidepressant drugs which enhance 5-HT neurotransmission via different mechanisms. The present studies were undertaken to determine whether the mirtazapine-paroxetine combination could induce an earlier and/or a greater effect on the 5-HT system than either drug alone. Using in vivo electrophysiological paradigms, the firing activity of dorsal raphe 5-HT neurons was decreased by 70% in rats treated with paroxetine (10 mg/kg/day, s.c.) for 2 days and was back to normal after 21 days. In contrast, a 2-day treatment with mirtazapine (5 mg/kg/day, s.c.) did not alter the firing of 5-HT neurons whereas it was increased by 60% after 21 days of treatment. A low dose of mirtazapine (5 mg/kg/day, s.c.x2 days) failed to offset the decremental effect of paroxetine on the 5-HT neuron firing activity, but a higher dose (10 mg/kg/day, s.c.x2 days) did attenuate the decremental effect of paroxetine. In the dorsal hippocampus, neither mirtazapine (5 mg/kg/day, s.c.) nor a paroxetine (10 mg/kg/day, s.c.) treatment altered the responsiveness of 5-HT(1A) receptors to microiontophoretically-applied 5-HT. Both in controls and in rats treated for 2 days with paroxetine alone, the administration of the 5-HT(1A) antagonist WAY 100635 (25-100 microg/kg, i.v.) did not change the firing activity of dorsal hippocampus CA(3) pyramidal neurons. However, WAY 100635 increased significantly the firing activity of these neurons in rats treated with mirtazapine alone but to a greater extent with both mirtazapine and paroxetine for 2 days. After 21 days of treatment, WAY 100635 increased to a greater degree the firing rate of CA(3) pyramidal neurons in rats which received the combination over rats given either drug alone. It is concluded that the mirtazapine-paroxetine combination shortened the delay in enhancing the tonic activation of postsynaptic 5-HT(1A) receptors and produced a greater activation of the postsynaptic 5-HT(1A) receptors than either drug given alone. The present results suggested that mirtazapine may have a faster onset of action than a SSRI, and that the co-administration of mirtazapine and paroxetine may accelerate the antidepressant response and as well as being more effective than either drug alone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10793320&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Regulation of phosphorylation of cyclic AMP response element-binding protein by paroxetine treatments.

Morinobu S, Russel DS, Sugawara S, Takahashi M, Fujimaki K.

Department of Psychiatry and Neurosciences, Hiroshima University School of Medicine, Japan.

The present study was undertaken to examine the effect of paroxetine, a selective serotonin reuptake inhibitor, on the phosphorylation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in the rat brain. Single administration of paroxetine significantly induces the phosphorylation of CREB in the rat frontal cortex and hippocampus in a time-dependent manner. Repeated administration of paroxetine attenuates CREB phosphorylation in response to acute paroxetine challenge. These findings suggest that the enhancement of intracellular signal transduction after the activation of serotonin receptors may be attenuated after chronic paroxetine treatment, and this attenuation may be, at least in part, involved in the therapeutic efficacy of paroxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10803801&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Paroxetine binding to the rat norepinephrine transporter in vivo.

Owens MJ, Knight DL, Nemeroff CB.

Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

BACKGROUND: The norepinephrine transporter (NET)/uptake site is an antidepressant-sensitive transporter located on plasma membranes of noradrenergic neurons and other specialized cells that remove norepinephrine (NE) from the synapse to terminate the actions of NE. The antidepressant paroxetine is believed to produce its therapeutic effects primarily by acting as a highly selective antagonist of the serotonin transporter (SERT). However, in vitro data indicates that paroxetine inhibits the NET. The present study was designed to determine whether paroxetine inhibits in NET in vivo. METHODS: Rats were administered paroxetine (6.5, 10.0, or 15.0 mg/kg/day) via osmotic minipumps for 1 week. Following attainment of steady state serum concentrations, cortical NET function was assessed by both [3H]-nisoxetine binding and [3H]-norepinephrine uptake assays conducted ex vivo. RESULTS: In unwashed brain homogenates, serum paroxetine concentrations greater than 100 ng/mL were positively correlated with the observed Kd for [3H]-nisoxetine. At [3H]-nisoxetine concentrations associated with 50% transporter occupancy in vehicle treated rats, [3H]-nisoxetine binding was decreased 21% and 34% in rats exhibiting serum paroxetine concentrations > 100 ng/mL and > 500 ng/mL, respectively. CONCLUSIONS: Although paroxetine is a very potent inhibitor of the SERT, paroxetine also inhibits the NET at serum concentrations > 100 ng/mL. This novel finding may underlie the broad therapeutic utility of paroxetine in mood and anxiety disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10812044&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of nortriptyline and paroxetine on measures of chaos of heart rate time series in patients with panic disorder.

Yeragani VK, Rao R.

Department of Psychiatry, Wayne State University School of Medicine, Detroit, MI, USA. vikramyershr yahoo.com

Tricyclic antidepressants have notable cardiac side effects, and this issue has become important due to the recent reports of increased cardiovascular mortality in patients with depression and anxiety. Several previous studies indicate that serotonin reuptake inhibitors (SRIs) do not appear to have such adverse effects. Apart from the effects of these drugs on routine 12-lead ECG, the effects on beat-to-beat heart rate (HR) and QT interval time series provide more information on the side effects related to cardiac autonomic function. In this study, we evaluated the effects of two antidepressants, nortriptyline (n=13), a tricyclic, and paroxetine (n=16), an SRI inhibitor, on HR variability in patients with panic disorder, using a measure of chaos, the largest Lyapunov exponent (LLE) using pre- and posttreatment HR time series. Our results show that nortriptyline is associated with a decrease in LLE of high frequency (HF: 0.15-0.5 Hz) filtered series, which is most likely due to its anticholinergic effect, while paroxetine had no such effect. Paroxetine significantly decreased sympathovagal ratios as measured by a decrease in LLE of LF/HF. These results suggest that paroxetine appears to be safer in regards to cardiovascular effects compared to nortriptyline in this group of patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14642980&dopt=Abstract paroxetine, Paxil, Paxil CR