paroxetine, Paxil
Antidepressant pharmacotherapy: economic evaluation of fluoxetine, paroxetine and sertraline in a health maintenance organization.

Sclar DA, Robison LM, Skaer TL, Galin RS, Legg RF, Nemec NL, Hughes TE, Buesching DP, Morgan M.

College of Pharmacy, Washington State University, Pullman, USA.

The present study was designed to compare direct health service expenditures, for the treatment of depression, among patients enrolled in a health maintenance organization, and prescribed one of three selective serotonin reuptake inhibitors, fluoxetine, paroxetine or sertraline. Information regarding depression-related health service use was derived from the computer archive of a network-model health maintenance organization system serving 700,000 beneficiaries. A total of 744 health maintenance organization beneficiaries were found to satisfy the study selection criteria. Multivariate regression analysis was used to determine the incremental influence of selected demographic, clinical, financial and provider characteristics on health service expenditures related to the treatment of depression (ICD-9-CM, or DSM-IV code 296.2) 1 year after the start of antidepressant pharmacotherapy. Multivariate findings indicate that treatment with paroxetine increases average expenditures for physician visits ($31.93; P < or = 0.05), psychiatric visits ($19.33; NS), laboratory tests ($2.35; P < or = 0.05), hospitalizations ($85.33; P < or = 0.05), psychiatric hospitalizations ($82.01; P < or = 0.05), and antidepressant pharmacotherapy ($63.72; P < or = 0.05), for a total per capita increase in health service use of $284.68 (P < or = 0.05), compared with treatment with fluoxetine. Sertraline treatment increases average expenditures for physician visits ($21.74; P < or = 0.05), psychiatric visits ($56.79; P < or = 0.05), laboratory tests ($1.21; P < or = 0.05), hospitalizations ($70.59; P < or = 0.05), psychiatric hospitalizations ($95.75; P < or = 0.05), and antidepressant pharmacotherapy ($69.85; P < or = 0.05), for a total per capita increase in health service use of $315.96 (P < or = 0.05), compared with treatment with fluoxetine. Economic comparisons between paroxetine and sertraline did not demonstrate any significant differences in expenditures for the health services examined.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8746607&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Serotonin2 receptors and the serotonin transporter in the schizophrenic brain.

Dean B, Hayes W, Opeskin K, Naylor L, Pavey G, Hill C, Keks N, Copolov DL.

Rebecca L. Cooper Laboratories, Mental Health Research Institute of Victoria, Parkville, Australia.

The binding of [3H]paroxetine and [3H]ketanserin to particulate membranes from frontal cortex of subjects who had or did not have schizophrenia was measured as was [3H]paroxetine binding to particulate membranes from the hippocampus and caudate nucleus. There was no change in either the affinity or density of [3H]ketanserin binding to membranes from the frontal cortex of subjects who had schizophrenia. Similarly, there was no difference in the density of [3H]paroxetine binding to membranes from subjects who had or did not have schizophrenia. The affinity of [3H]paroxetine binding in the frontal cortex and putamen did not differ in subjects who had schizophrenia. By contrast, there was a significant decrease in the affinity of [3H]paroxetine binding to the hippocampal membrane from subjects who had schizophrenia (0.40 +/- 0.06 nM vs 0.26 +/- 0.02 nM; p < 0.05). Furthermore, this difference was more apparent in the subjects who had schizophrenia and committed suicide (0.49 +/- 0.09 nM) than it was in those who had schizophrenia but did not commit suicide (0.32 +/- 0.09 nM). As [3H]ketanserin binds to the serotonin2 receptor our data suggest that this receptor is not changed in the Brodmann's area 9 of the frontal cortex. By contrast, [3H]paroxetine binds to the serotonin transporter and therefore our data suggest that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8788497&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The serotonin transporter from human brain: purification and partial characterization.

Rotondo A, Giannaccini G, Betti L, Chiellini G, Marazziti D, Martin C, Lucacchini A, Cassano GB.

Institute of Psychiatry, University of Pisa, Italy.

The serotonin (5-HT) transporter from human striatum was solubilized by digitonin and purified by affinity chromatography. The native protein-detergent complex had a molecular mass of 205 kDa, as estimated by gel-exclusion chromatography of the eluates obtained from affinity chromatography. The purified 5-HT transporter migrated as a single band of 67 kDa in SDS-PAGE. To clarify the spatial relationships between the binding sites of the tricyclic antidepressants, as [3H]-imipramine, and of the selective serotonin reuptake inhibitors, as [3H]-paroxetine, on the 5'HT transporter, both radioligands were used to label it in the purification steps. [3H]-paroxetine bound with the same affinity to a single high-affinity site on both membrane and purified preparations. [3H]-imipramine labeled a high- and a low-affinity site on parent membranes, whereas it bound to a single high-affinity site on the purified extract. Tricyclic antidepressants, selective serotonin reuptake inhibitors and 5-HT itself displaced [3H]-paroxetine and [3H-]imipramine from their high-affinity binding sites on both the membrane-bound and the purified 5-HT transporter in a monophasic fashion with Hill coefficients close to unity. Furthermore, both [3H]-paroxetine and [3H]-imipramine displayed a similar maximum binding capacity on an identical protein of 205 kDa. Our results suggest overlapping binding sites for tricyclic antidepressants, selective serotonin reuptake inhibitors and 5-HT on the 5-HT transporter.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8813248&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Changes in the serotonin transporter in the hippocampus of subjects with schizophrenia identified using [3H]paroxetine.

Naylor L, Dean B, Opeskin K, Pavey G, Hill C, Keks N, Copolov D.

Rebecca L. Cooper Laboratories, Mental Health Research Institute of Victoria, Parkville, Australia.

[3H]paroxetine binding to membrane from hippocampus, obtained at autopsy, from 24 schizophrenic and 24 non-schizophrenic subjects has been measured. The affinity of [3H]paroxetine binding to hippocampal membrane was decreased in subjects with schizophrenia (Kd = 0.50 +/- 0.04 vs. 0.24 +/- 0.02nM; mean +/- S.E.M. p < 0.001) but was not different in schizophrenic subjects who had or had not committed suicide (Kd = 0.50 +/- 0.07 vs. 0.50 +/- 0.04nM). The density of [3H]paroxetine binding sites did not differ between the schizophrenic and non-schizophrenic subjects. For the schizophrenic subjects, there was no relationship between ante-mortem neuroleptic drug treatment and [3H]paroxetine binding to the hippocampal membrane. Finally, this study has shown that neuroleptic drug treatment of rats does not alter [3H]paroxetine binding to the hippocampal membranes. Thus, it would seem that the changes in the affinity of [3H]paroxetine binding to the hippocampus of schizophrenic subjects are not likely to be due to neuroleptic drug treatment but may be involved in the pathology of the illness.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8836936&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
The effects of paroxetine given repeatedly on the 5-HT receptor subpopulations in the rat brain.

Maj J, Bijak M, Dziedzicka-Wasylewska M, Rogoz R, Rogoz Z, Skuza G, Tokarski T.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Effects of paroxetine (10 mg/kg PO, twice daily, 14 days) on 5-HT receptor subpopulations in the brain were evaluated pharmacologically, electrophysiologically and biochemically in male Wistar rats. Imipramine was used for comparison. Repeated paroxetine antagonized the 8-OH-DPAT-induced behavioural syndrome (a 5-HT1A effect); imipramine showed similar, yet weaker, activity. The 5-HT-or 8-OH-DPAT-induced inhibition of population spikes in hippocampal slices was increased by both those repeated antidepressants. Repeated (or acute) paroxetine decreased the density of and increased the affinity for 5-HT1A receptors ([3H]-8-OH-DPAT used as ligand) in the hippocampus, while imipramine induced opposite effects. m-Chlorophenyl piperazine (m-CPP)-evoked exploratory hypoactivity, a 5-HT2C effect, was reduced by repeated paroxetine, but not by imipramine. Either of the antidepressants given repeatedly antagonized TFMPP-induced hyperthermia (another putative 5-HT2C effect). 5-HTP-induced head twitches (a 5-HT2A effect) were inhibited by repeated paroxetine or imipramine. Either antidepressant given repeatedly decreased the density of 5-HT2A receptors ([3H]-ketanserin as a ligand) in the brain cortex, but did not change their affinity. The present results indicate that paroxetine given repeatedly induces secondary changes in 5-HT2 receptors, which lead to reduction of the 5-HT2 neurotransmission (reduced responsiveness of 5-HT2 postsynaptic receptors). The consequences of the secondary changes in 5-HT1A receptors, found here still await clarification.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8880946&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of fluvoxamine on 5-hydroxytryptamine uptake, paroxetine binding sites and ketanserin binding sites in the Japanese monkey brain and platelets, in vivo and in vitro.

Goto S, Egashira T, Wada Y, Takayama F, Yamanaka Y.

Department of Pharmacology, Oita Medical University, Japan.

We investigated the in vitro effects of fluvoxamine on 3H-paroxetine binding and 3H-monoamine uptake in monkey cerebral cortex in comparison with those of other antidepressants. Fluvoxamine selectively inhibited 3H-5-hydroxytryptamine (5-HT) uptake and 3H-paroxetine binding. However, it did not alter 3H-norepinephrine or 3H-dopamine uptake. In addition, we examined the effects of chronic treatment with fluvoxamine (5 mg/kg per day, p.o.) on 5-HT uptake sites that bind 3H-paroxetine and 5-HT2 receptors that bind 3H-ketanserin, in monkey brains and platelets. Chronic treatment with fluvoxamine affected neither the paroxetine binding sites nor the kentanserin binding sites of the brains and platelets. These results suggest that long-term treatment with fluvoxamine does not affect either the 5-HT uptake sites or 5-HT2-receptors of 5-HT neurons in monkey brain in spite of its strong inhibitory effect on 5-HT uptake in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8886926&dopt=Abstract paroxetine, Paxil, Paxil CR



paroxetine, Paxil
Effect of pindolol on the function of pre- and postsynaptic 5-HT1A receptors: in vivo microdialysis and electrophysiological studies in the rat brain.

Romero L, Bel N, Artigas F, de Montigny C, Blier P.

Department of Neurochemistry, CID, Consejo Superior de Investigaciones Cientificas (CSIC), Barcelona, Spain.

In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8887989&dopt=Abstract paroxetine, Paxil, Paxil CR