paroxetine, Paxil
The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder.

Schruers K, Griez E.

Department of Psychiatry and Neuropsychology, Research Institute Brain and Behaviour, Maastricht University, 6200 AB Maastricht, The Netherlands. koen.schruers pn.unimaas.nl

Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.

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paroxetine, Paxil
Negative symptoms of schizophrenia are improved by the addition of paroxetine to neuroleptics: a double-blind placebo-controlled study.

Jockers-Scherubl MC, Bauer A, Godemann F, Reischies FM, Selig F, Schlattmann P.

Department of Psychiatry, Charite University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany. maria.jockers charite.de

Despite the availability of atypical antipsychotics, the treatment of negative symptoms in schizophrenia remains a challenge. This study was designed to confirm the positive effect observed in our pilot study with paroxetine as augmentation to antipsychotics in the treatment of negative symptoms in chronic schizophrenia. Twenty-nine patients with chronic schizophrenia, as defined by DSM-IV, who scored at least 20 points on the negative subscale of the Positive and Negative Syndrome Scale (PANSS) were randomized for treatment with 30 mg paroxetine or placebo in a double-blind, placebo-controlled study for 12 weeks. Ratings included the PANSS, the Hamilton Rating Scale for Depression (HAM-D) and scales for extrapyramidal side-effects. An intention-to-treat analysis was based on the 25 patients who were available for at least one follow-up assessment. The last observation carried forward principle was applied. The mean score of the negative subscale of the PANSS decreased in both groups. Using an analysis of covariance, there was a significant treatment effect with paroxetine compared to placebo with respect to negative symptoms (-4.53; 95% confidence interval -9.054 to -0.015). The mean HAM-D scores remained almost constant. The study suggests the efficacy of paroxetine with respect to the treatment of negative symptoms in chronic schizophrenia.

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paroxetine, Paxil
Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics.

Javors MA, Seneviratne C, Roache JD, Ait-Daoud N, Bergeson SE, Walss-Bass MC, Akhtar FZ, Johnson BA.

South Texas Addiction Research and Technology (START) Center, and Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. javors uthscsa.edu

Expression rates of long (L) and short (S) alleles of the serotonin (5-HT) transporter (5-HTT) gene have been shown to differ under various circumstances. We compared 5-HTT uptake (function) level and paroxetine binding (density) in platelets of alcoholics as indices of 5-HTT expression rate among LL, LS, and SS genotypes. Concentration curves of [3H]5-HT and [3H]paroxetine were used to quantify the equilibrium constant (Km) and maximum 5-HT uptake rate (Vmax) for 5-HTT uptake into intact platelets and the dissociation constant (Kd) and maximum specific binding density (Bmax) for paroxetine binding to platelet membranes, respectively. Genotypes were determined using electrophoresis with fluorescent markers. Vmax for 5-HTT uptake did not correlate with Bmax for paroxetine binding (r=-0.095, P=0.415). Means of Vmax and Bmax did not differ in a statistically significant manner among LL, LS, and SS genotypes in these alcoholic subjects. However, Vmax for LL and SS appeared to have a bimodal distribution, so the percentage of subjects with Vmax <200 fmol/min-10(7) platelets was statistically significantly higher in LL than in SS (51.5% vs. 22.7%, respectively), with an odds ratio of 3.6 (P<0.05). The percentage of Vmax <200 fmol/min-10(7) platelets for LS was 39.3% (not significant vs. LL or SS). Previous studies of healthy human controls have shown that 5-HTT density in raphe nuclei and 5-HTT uptake in platelets are higher in the LL genotype than in S carriers. Our findings in currently drinking alcoholics support the hypothesis that those with the LL genotype of the 5'-HTTLPR region of the 5-HTT gene have reduced 5-HTT function.

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paroxetine, Paxil
The different roles of 5-HT(2) and 5-HT(3) receptors on antinociceptive effect of paroxetine in chemical stimuli in mice.

Kesim M, Duman EN, Kadioglu M, Yaris E, Kalyoncu NI, Erciyes N.

Department of Pharmacology, Karadeniz Technical University School of Medicine, Trabzon, Turkey.

Serotonin (5-HT) is known to be an important mediator in pain modulation. Some centrally acting agents, like selective serotonin reuptake inhibitors (SSRIs), modulate pain. Activation of the endogenous opioid mechanisms or potentiation of analgesic effect by serotonergic and/or noradrenergic pathways might be involved in antinociception of SSRIs. However, peripheral mechanisms of nociception are not clear. In this study, the antinociceptive effect of paroxetine, its interaction with the opioidergic system and serotonin receptors were tested using the writhing test in mice. Paroxetine (5, 10, 20 mg/kg) induced an antinociceptive effect following i.p. administration in writhing test. For the groups in which the antagonists were tested, the dose of paroxetine that caused a significant and equipotent analgesic effect similar to 0.5 mg/kg morphine was selected. Naloxone significantly antagonized the antinociceptive effects of both paroxetine and morphine in a similar pattern and magnitude. Ketanserin (5-HT(2)-receptor antagonist) or ondansetron (5-HT(3)-receptor antagonist) alone did not alter the nociceptive action of acetic acid. While the antinociceptive effect of paroxetine was highly potentiated by ketanserin, ondansetron reduced that antinociception. In conclusion, our results indicate that the antinociceptive effect of paroxetine mainly depends on central opioidergic and serotonergic mechanisms. Peripheral serotonergic mechanisms/receptors may contribute to this antinociceptive effect, especially by 5-HT(3)-receptor subtypes.

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paroxetine, Paxil
COMORBID CONDITIONS.

[No authors listed]

Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain. 2004;110:689-696. Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU-maintenance or WU-M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU-M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7-second duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 seconds by stimuli delivered at 0.16 and 0.08 Hz (WU-M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU-M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU-M, and increased WU-related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU-M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization. Comment: Interesting study as we become more and more concerned with central senitization in primary headache patients.-Stewart J. Tepper, MD Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292:338-343. Background: The relation between the 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 one of three 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 four antidepressant drugs. Participants could have used only one of these antidepressants and had to have received at least one 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 four 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 (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 four drugs on people aged 10 to 19 years. Comment: This is an interesting study by the Boston collaborative group trying to unravel whether any of the antidepressants used in young people to treat a first attack of depressive illness were more likely to be linked to suicidal behavior. This was carried out using the UK General Practice Database which allows record linkage between diagnosis, treatment, and outcomes. As a primary care practitioner who contributes data to the GPRD, I am concerned that this study does not have the statistical power to exclude the possibility of an association. The authors rightly acknowledge the limited data upon which their conclusion is based. Moreover, the GPRD data base does not allow for the severity of depression to be categorized, hence the statement that "the 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" cannot be excluded using the GPRD.-David S. Millson, MD March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J, Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. Background: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective: To evaluate the effectiveness of four treatments among adolescents with major depressive disorder. Design, Setting, and Participants: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 and 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P= 0.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P= .02) and CBT alone (P= .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P= .01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the two fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all four treatment groups. Fluoxetine with CBT showed the greatest reduction (P= .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. Comment: The evidence is accumulating that the suicide risk may be up slightly due to the activating effects of the SSRIs when initially treating severe depression, especially in adolescents, though apparently less so with fluoxetine. The risk is reduced by having the patient simultaneously undergo Cognitive Behavioral Therapy (CBT). In headache management, we rarely have such severely depressed patients when we initiate therapy, but depression is co-morbid with migraine, and discussion of depression and mood is important before initiation of SSRI therapy.-Stewart J. Tepper, MD Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004;24:6590-6599. Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness. Comment: Valproate has important structural effects on the brain in patients with bipolar illness, where underlying structural differences ("morphometic deficits") exist. Morphometic differences are also present in epilepsy patients, and it may not be a stretch to assume them in primary headache patients. So, the chronic effects of valproate are biochemical, electrical, and structural, and we are just beginning to understand them.-Stewart J. Tepper, MD.

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paroxetine, Paxil
PET Studies of the Effect of the Antidepressant Drugs Nefazodone or Paroxetine on [11C]Raclopride Binding in Human Brain.

Fowler JS, Wang GJ, Volkow ND, Ieni J, Logan J, Pappas N, Dewey SL.

Chemistry and Medical Departments, Brookhaven National Laboratory, Upton, NY, USA

Serotonin modulates dopamine release in the striatum. In this study we set out to determine whether nefazodone and paroxetine, two antidepressant drugs that interact with the brain serotonin system, produce detectable changes in synaptic dopamine in vivo in the human brain using positron emission tomography (PET) and [11C]raclopride, a dopamine D-2 receptor specific radiotracer that is sensitive to changes in synaptic dopamine. Three normal healthy human volunteers had 4 PET/[11C]raclopride scans each in 2 sessions. In the first session, subjects had a baseline [11C]raclopride scan and a second scan 1 hour following the oral administration of either nefazodone (200 mg PO) or paroxetine (20 mg PO). Four to 6 weeks later, in a second PET/[11C]raclopride session, the same subjects received the other drug for comparison. Neither nefazodone nor paroxetine produced significant changes in [11C]raclopride binding. This and other reports in the literature indicate that different drugs that affect the serotonin system do not produce consistent and predictable changes in [11C]raclopride binding and that a full understanding of their actions on serotonin and the associated changes in dopamine requires further investigation.

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paroxetine, Paxil
The four-plates test-retest paradigm to discriminate anxiolytic effects.

Ripoll N, Nic Dhonnchadha BA, Sebille V, Bourin M, Hascoet M.

Neurobiologie de l'anxiete et de la depression, Faculte de Medecine, EA 3256, 1 rue Gaston Veil, BP 53508, 44035, Nantes cedex 01, France, Michel.Bourin univ-nantes.fr.

RATIONALE: Animal models of anxiety such as the four-plates test (FPT) enable the detection of an anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZD anxiolytic compounds such as the antidepressants paroxetine and venlafaxine. Retesting mice in animal models of anxiety markedly alters the behavioural profile of various drugs. OBJECTIVES: The aim of this study was first to investigate the function of GABA(A)/BZD receptor and passive avoidance acquisition in the FPT "test-retest". The second aim of this study was to evaluate the capacity of the FPT to discriminate BZDs from other non-BZD anxiolytics in experienced mice. METHODS: The FPT was performed in naive and experienced mice (submitted to the test 24 h previously). The drugs studied were two BZDs, diazepam (1 mg/kg) and alprazolam (0.25 mg/kg); flumazenil, a GABA(A) receptor antagonist (8 mg/kg); atropine sulphate, a muscarinic cholinergic receptor antagonist (4 mg/kg) known for its amnesic properties; paroxetine, a selective serotonin reuptake inhibitor (4 and 8 mg/kg); venlafaxine, a serotonin and noradrenalin reuptake inhibitor (4 and 16 mg/kg); and DOI, a 5-HT(2A) agonist (1 mg/kg). RESULTS: Our results reveal an increase of anxiety (decrease of punished passages) in saline-experienced mice. Diazepam, alprazolam, paroxetine and venlafaxine did not prevent the increase in anxiety during retest, revealing a passive avoidance acquisition. Flumazenil did not modify the anxiogenic-like behaviour of experienced mice. In contrast, atropine seems to oppose the increase of anxiety; however, its effect is weak and disputable. DOI was the only anxiolytic compound able to oppose the decrease of punished passages of experienced mice. CONCLUSION: Anxiogenic behaviour on retesting indicates aversive learning. The protocol test-retest is unable to discriminate between the anxiolytic effect of BZDs from that of paroxetine or venlafaxine. However, this modified model may constitute a new tool to investigate other neural pathways implicated in anxiety.

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