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ACS Chemical Neuroscience Sep 2019The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily...
The serotonin transporter (SERT) is the primary target for the selective serotonin reuptake inhibitors (SSRIs). However, the structural basis for the extraordinarily high binding affinity of the widely prescribed SSRI, paroxetine, to human SERT (hSERT) has not yet been fully elucidated. Our previous findings unveiled a plausible ambiguity in paroxetine's binding orientations that may constitute an integral component of this SSRI's high affinity for hSERT. Herein, we investigate factors contributing to paroxetine's high affinity by modifying both the ligand and the protein. We generated a series of bromine (Br)-containing derivatives and found that the one in which the 4-F of paroxetine had been replaced with the chemically similar but more electron-rich Br atom () had the highest affinity. By comparatively characterizing the binding of paroxetine and to both wild type (WT) and a construct harboring a paroxetine-sensitive mutation in the binding cavity, we identified a mechanistic determinant responsible for the pose ambiguity of paroxetine, which can guide future drug design.
Topics: Binding Sites; Bromine; Crystallography, X-Ray; HEK293 Cells; HeLa Cells; Humans; Paroxetine; Protein Binding; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 31424193
DOI: 10.1021/acschemneuro.9b00375 -
Depression and Anxiety 2001The objective of this study was to compare the efficacy and tolerability of paroxetine to matched placebo in adults with co-occurring social anxiety disorder and alcohol... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The objective of this study was to compare the efficacy and tolerability of paroxetine to matched placebo in adults with co-occurring social anxiety disorder and alcohol use disorder. Outcome measures included standardized indices of social anxiety and alcohol use. Fifteen individuals meeting DSM-IV criteria for both social anxiety disorder and alcohol use disorder were randomized to treatment. Paroxetine (n = 6) or placebo (n = 9) was given in a double-blind format for 8 weeks using a flexible dosing schedule. Dosing began at 20 mg/d and increased to a target dose of 60 mg/d. There was a significant effect of treatment group on social anxiety symptoms, where patients treated with paroxetine improved more than those treated with placebo on both the Clinical Global Index (CGI) and the Liebowitz Social Anxiety Scale (Ps < or = 0.05). On alcohol use, there was not a significant effect of treatment on quantity/frequency measures of drinking, but there was for the CGI ratings (50% paroxetine patients versus 11% placebo patients were improvers on drinking, P < or = 0.05). This pilot study suggests that paroxetine is an effective treatment for social anxiety disorder in individuals with comorbid alcohol problems, and positive treatment effects can be seen in as little as 8 weeks. Further study is warranted to investigate its utility in helping affected individuals reduce alcohol use.
Topics: Adolescent; Adult; Aged; Alcoholism; Comorbidity; Diagnosis, Dual (Psychiatry); Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Paroxetine; Phobic Disorders; Pilot Projects; Treatment Outcome
PubMed: 11754136
DOI: 10.1002/da.1077 -
The Journal of Clinical Psychiatry Nov 2011
Topics: Antidepressive Agents, Second-Generation; Depressive Disorder, Major; Humans; Mental Disorders; Paroxetine; Randomized Controlled Trials as Topic; Suicide
PubMed: 22127198
DOI: 10.4088/JCP.11lr07373 -
Neuropharmacology Dec 2019The serotonin transporter (SERT) is one of the primary targets for medications to treat neuropsychiatric disorders and functions by exploiting pre-existing ion gradients...
The serotonin transporter (SERT) is one of the primary targets for medications to treat neuropsychiatric disorders and functions by exploiting pre-existing ion gradients of Na, Cl, and K to translocate serotonin from the synaptic cleft into the presynaptic neuron. Although recent hSERT crystal structures represent a milestone for structure-function analyses of mammalian neurotransmitter:sodium symporters, they are all derived from thermostabilized but transport-deficient constructs. Two of these structures are in complex with paroxetine, the most potent selective serotonin reuptake inhibitor known. In this study, by carrying out and analyzing the results of extensive and comparative molecular dynamics simulations while also re-evaluating the transport and binding properties of the thermostabilized constructs, we identified functionally important structural elements that are perturbed by these mutations, revealed unexpected dynamics in the central primary binding site of SERT, and uncovered a conceivable ambiguity in paroxetine's binding orientation. We propose that the favored entropy contribution plays a significant role in paroxetine's extraordinarily high affinity for SERT. Our findings lay the foundation for future mechanistic studies and rational design of high-affinity SERT inhibitors. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Topics: Biological Transport, Active; Entropy; Humans; Kinetics; Models, Molecular; Molecular Dynamics Simulation; Mutation; Paroxetine; Protein Binding; Protein Conformation; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors
PubMed: 30391505
DOI: 10.1016/j.neuropharm.2018.10.040 -
Successful Treatment of Inappropriate Sexual Behavior and Disinhibition in Dementia With Paroxetine.Journal of Clinical Psychopharmacology
Topics: Humans; Paroxetine; Sexual Behavior; Problem Behavior; Dementia
PubMed: 36584258
DOI: 10.1097/JCP.0000000000001644 -
Journal of Child and Adolescent... 2001Paroxetine has repeatedly been shown to be effective in the treatment of panic disorder (PD) in adults, and, according to previous case observations, it may be useful in... (Clinical Trial)
Clinical Trial
Paroxetine has repeatedly been shown to be effective in the treatment of panic disorder (PD) in adults, and, according to previous case observations, it may be useful in treating children and adolescents with PD as well. This preliminary naturalistic study examines effectiveness and safety of paroxetine in the treatment of children and adolescents with PD. A chart review was conducted on 18 patients with Diagnostic and Statistical Manual of Mental Disorders PD admitted to the Division of Child Neurology and Psychiatry and to the Department of Psychiatry at the University of Pisa. Paroxetine was given at an initial mean dosage of 8.9 +/- 2.1 mg/day and was gradually increased up to 40 mg/day, depending on clinical response and side effects. Clinical status was assessed with the Clinical Global Impression (CGI) and adverse effects were assessed retrospectively at each visit. Patients with final CGI-Improvement scores of 1 or 2 were considered responders. Mean paroxetine treatment duration was 11.7 +/- 8.3 months, with a mean final dosage of 23.9 +/- 9.8 mg/day (range, 10-40 mg/day). No patient had to interrupt the treatment because of side effects. Fifteen patients (83.3%) were considered responders. The mean change on the CGI-Severity scale was statistically significant (p < 0.0001). Paroxetine was well tolerated and effective in the treatment of PD in these children and adolescents.
Topics: Adolescent; Antidepressive Agents, Second-Generation; Child; Female; Humans; Male; Panic Disorder; Paroxetine; Psychiatric Status Rating Scales
PubMed: 11436954
DOI: 10.1089/104454601750284054 -
Journal of the American Academy of... Nov 2002
Topics: Adolescent; Depressive Disorder, Major; Drug Monitoring; Humans; Imipramine; Paroxetine; Selective Serotonin Reuptake Inhibitors
PubMed: 12410065
DOI: 10.1097/00004583-200211000-00001 -
European Neuropsychopharmacology : the... Jan 2004Since hyperventilation and shortness of breath are characteristic features of panic attacks, and since the attacks can be elicited by CO(2) inhalation, an involvement of... (Comparative Study)
Comparative Study
Since hyperventilation and shortness of breath are characteristic features of panic attacks, and since the attacks can be elicited by CO(2) inhalation, an involvement of central or peripheral chemoreceptors in the pathophysiology of panic disorder has been suggested. Prompted by clinical reports suggesting that the susceptibility to spontaneous as well as CO(2)-induced anxiety and hyperventilation is attenuated by serotonin reuptake inhibitors (SRIs), we undertook the present study in order to explore the possible effect of an SRI, paroxetine, on baseline respiration and CO(2)-induced hyperventilation in freely moving Wistar rats. A significant increase in baseline respiratory rate was seen both after 5 and 15 weeks of treatment with paroxetine. CO(2) exposure induced a dose-dependent increase in respiratory rate, but not tidal volume, in both paroxetine-treated rats and controls; this response was reduced after 15 weeks of paroxetine treatment, but not after 5 weeks of treatment. We suggest that an influence on the regulation of respiration may be of importance for the anti-panic effect of SRIs.
Topics: Animals; Carbon Dioxide; Male; Panic Disorder; Paroxetine; Rats; Rats, Wistar; Respiration
PubMed: 14659984
DOI: 10.1016/s0924-977x(03)00044-0 -
The American Journal of Psychiatry Oct 1994
Topics: Humans; Obsessive-Compulsive Disorder; Paroxetine; Psychiatric Status Rating Scales; Treatment Outcome
PubMed: 8092350
DOI: 10.1176/ajp.151.10.1523b -
The Journal of Clinical Psychiatry Dec 1992Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI). The present study assessed the efficacy and tolerability of paroxetine against placebo in... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
Paroxetine is a potent and selective serotonin reuptake inhibitor (SSRI). The present study assessed the efficacy and tolerability of paroxetine against placebo in depressed outpatients.
METHOD
A double-blind, parallel-group study was undertaken in four stand-alone centers. Patients aged 18-65 years, meeting DSM-III criteria for major depression, and having a Hamilton Rating Scale for Depression (HAM-D) score > or = 18 on the first 17 items of the HAM-D-21 were randomized to paroxetine or placebo for 6 weeks of treatment. Efficacy outcome variables included the HAM-D, the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impressions Scale (CGI), and the Covi Anxiety Scale. Tolerability was assessed by asking a non-leading question. Routine laboratory safety and vital sign data from all four centers were pooled. The primary analysis used the intention-to-treat sample and for efficacy variables the last-observation-carried-forward data set was employed. Statistical methods included one-way analysis of variance for parametric and Fisher exact test for nonparametric variables.
RESULTS
Significant differences (p < or = .05) were found between paroxetine and placebo on the HAM-D and CGI by Week 2 and on all efficacy outcome variables by Week 4. Improvement on the HAM-D sleep factor occurred 2 weeks prior to that seen on the retardation factor. Similar results were obtained when an adequate treatment group (therapy for > or = 28 days) was considered. A full clinical response (CGI-severity of illness score 1 or 2) was seen in over 40% of subjects. Adverse events were more common for paroxetine compared with placebo (p < or = .01). Somnolence was twice more common than nervousness. Dropout due to adverse events was similar between therapies. Paroxetine had no clinically significant effect on laboratory safety data or vital signs.
CONCLUSION
Paroxetine was an effective, well tolerated, and safe antidepressant. Side effects were typical of the SSRI class of drugs. Symptoms indicative of a nonalerting profile were more common than those associated with alerting effects.
Topics: Adolescent; Adult; Aged; Ambulatory Care; Arousal; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Nausea; Paroxetine; Placebos; Psychiatric Status Rating Scales; Severity of Illness Index
PubMed: 1487471
DOI: No ID Found