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P.6. Other topics
[2] Abbar M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D, Ferreira M, Lambercy C, Mouthon D, Paoloni-Giacobino A,Vessaz M, Malafosse A, Buresi C. Suicide attempts and the tryptophan hydroxylase gene. Mol Psychiatry. 2001; 6(3): 268-73.
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Risperidone in children and adolescents with conduct disorder
I. Drtilkovfi, P. Theiner, J. Blazek. Clinic of Psychiatry Brno, Department of chiM psychiatry, Brno, Czech Republic
Objective: It is generally accepted that aggression in chilhood predicts poor prognosis and serious antisocial behavior in adulthood. A variety of medictions have been tried in the management of behaviours problems in children, including lithium, clonidine, carbamazepine, stimulants, SSRI and conventional neuroleptics. Conventional neuroleptic agents are the commonly prescribed drugs in this population, however, side effects such as extrapyramidal symptoms and risk of tardive dyskinesia, excessive sedation and cognitive blunting limit their use. Opened and controlled investigations have shown risperidone is effective for reducing agressive and self-injurious behaviour in mentally retarded children and may ameliorate symptoms of aggression in youths with conduct disorder. Method: We initiated a retrospective study in order to examine the safety, tolerability and efficacy of risperidone in children and adolescents with conduct disorders. The sample included 34 patients (32 boys and 2 girls) - 28 in-patients and 6 out-patients. All subjects were having DSMIV criteria for conduct disorder as a primary diagnosis. The ages of the patients ranged from 5 to15 years, the mean age was 9,74 years. Patients received 1,29mg of risperidone for 16,25 days in average, medication could be increased during the first 2 weeks of the study from an initial dose of 0,25 mg or 0,50 mg each morning, depending on patients' weight. The treatment response was monitored by means of the improvement in CGI (which assesses illness severity and global improvement) and the TQ (Teacher Questionnaire - Conners, 1989), which assesses for a variety of behavioral and emotional difficulties. Results: Therapeutic benefits were sustained in all cases, statistically significant improvements were found in the CGI scale (p<0.05) and the TQ (p<0.05), For the 2 patients with comorbid chronic tics a significant reduction in tic frequency was observed. Risperidone had favourable effect on TQ subscale score of inattention and overactivity in patients with comorbid ADHD. The most common side effects were tiredness, somnolence and headache. In general, these side effects were mild and transient. No subject developed any abnormal involuntary movements and no subject required treatment with benztropine. We failed to note in any of the subjects sings of behavioral activation, anticholinergic side effects, dystonia or significant changes in blood pressure and heart rate. These data suggest that initiating risperidone treatment at low doses as well as implementing a gradual titration strategy can significantly reduce the risk of EPS. Conclusions: Risperidone appeared to be safe and effective in ameliorating symptoms of conduct disorders in this age group. Supported by grant IGA MZ ER 6520-5
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Effects of chronic treatment of ondansetron, on pentylenetetrazole-induced seizures
H. Sangraula. B.P. Koirala Institute of Health Sciences, Dept. of Pharmacology, Dharan, Nepal
Background:
The link between serotonergic (5-HT) and GABAergic system in brain is little known. Objective: To investigate the interaction between 5-HT and GABA with the chronic administration of ondansetron (ODS, a 5-HT3 receptor antagonist) on pentylenetetrazol (PTZ, a GABAA antagonist)-induced seizures. Methods: Mice of either sex (25-35 g) were treated with Ondansetron (0.5-2 mg/kg intraperitoneally, n=10) or saline (n=10) daily for 30 days. On day 31, they were administered a convulsive dose of PTZ (60 mg/kg, subcutaneously, and various behavioral convulsive parameters were studied. Animals were treated as per the institute's ethical guidelines. Results: PTZ produced frank tonic clonic convulsions in untreated mice. Ondansetron dose dependently protected against PTZ induced seizures. The number of mice developing convulsions was significantly less in ODS treated group compared to saline treated group (4 vs 8), the severity of convulsions was much less, and onset of convulsions was also significantly delayed in ODS treated group compared to vehicle treated group (3.52± 0.21 rain vs 2.42-- 0.19 min, p<0.01). Conclusion: The results show that chronic blockade of 5-HT3 receptor with ondansetron may protect against seizures even in seizure prone individuals with reduced GABA activity as evidenced by administration of PTZ. Further studies are required to substantiate the findings.
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Effect of restraint stress on the memory of Wistar rats in the passive avoidance task; time relationship between footshock and stress applications
V. Klenerova, O. Kaminsky, P. Sida, S. Hynie. Charles University,
1st Medical Faculty, Department of Pharmacology, Prague, Czech Republic Our previous studies demonstrated an impaired passive avoidance learning in two rat strains after restraint combined with water immersion (IMO+C). This stressor (lasting for 60 rain) administered 60 min before the acquisition trial impaired passive avoidance response learning to the degree that can be considered as amnesia (l). In this work we were interested in the effects of IMO+C on Wistar rats in dependence of time relationship between footshock and stressor application. IMO+C was applied 4 and 1 hour before footshock, and immediately and 4 hours after this aversive stimulus. We used Wistar rats of body weight 200+12 g that had free access to a standard pellet food and water. Treatment of animals was in accordance with the Declaration of Helsinki Guiding Principles on Care and Use of Animals (DHEW Publication, NHI 8023). We used a shuttle-cage (Coulbourn Instruments Inc., Penn., USA)(2). The starting compartment was illuminated and the shock compartment was dark. A stainless steel bar floor was used to delivery of scrabled constant current. WinLinc software was used for designing passive avoidance testing and to process experimental data. After 2 days lasting habituation phase we applied IMO+C and acquisition trial was performed. Twenty-four hours
17.6. Other topics later the retention trial was done. The results are expressed as latencies in seconds. All data were statistically evaluated and the criterion for statistical significance was p<0.05. All rats acquired passive avoidance response during two days of pre-acquisition phase. After application of footshock the control animals showed in the retention phase latencies to enter the shock compartment that approached the time limit of 180 seconds. Application of the stressor one hour before or immediately after the footshock revealed nearly complete amnesia. Rats that received IMO+C four hours before or four hours after the application of an aversive stimulus did not significantly differ from the control animals. Our results indicate that passive avoidance testing is a very suitable procedure for memory testing of stressed rats and that the effect of stressor is very sensitive to the time of its application in relation to the administration of an aversive stimulus. These findings can have many practical implications. This work was supported by Grant IGA of Ministry of Health ER NO 1-6627-3 and MSM 1111 0000 1.
References [1] Klenerova V, Kaminsky O., Sida P., Krejci I., Hlinak Z., and Hynie S. (2002) Impaired passive avoidance acquisition in Sprague-Dawley and Lewis rats after restraint and cold stress. Behav. Brain Res.(in press). [2] Kaminky O., Klenerova V, Stohr J., Sida E, Hynie S. (2001) Differences in the behaviour of Sprague-Dawley and Lewis rats during the repeated passive avoidance procedure: Effect of amphetamine. Pharmacol. Res. 44, 117-122.
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Differential effects of serotonin reuptake inhibitors on blood flow increases to pelvic nerve stimulation in vagina and clitoris in female rabbits
J. Angulo 1, R Cuevas 1, S. Gupta 2, I.S. De Tejada 1, B. Cuevas 1 .
1Fundaci6n para la Inuestigacirn y el Desarrollo en, Madrid, Spain," 2Forest Laboratories, New York, NY,, U.S.A. Sexual dysfunction is commonly observed in women and men under treatment with selective serotonin reuptake inhibitors (SSRIs), which are extensively used as antidepressant drugs. We have previously reported that chronic as well as acute administration of the SSRI paroxetine, but not citalopram, impairs erectile responses in male rats and reduces the production of nitric oxide (NO), which is a key mediator of penile erection. NO is also involved in the relaxation of vaginal and clitoral smooth muscle and facilitates the increase of blood flow in these organs after sexual stimulation. These processes are thought to be essential in the female sexual response. The aim of this study was to determine the effects of acute administration of paroxetine, escitalopram (the S-enantiomer of citalopram) and venlafaxine on the increases in blood flow in vagina and clitoris induced by pelvic nerve electrical stimulation (PNES) in a female rabbit model. Application of PNES produced consistent and frequency-related blood flow increases in vagina and clitoris of anesthetized female rabbits. These parameters were not affected by the treatment with vehicle (20% HP[SCD) (106.0% and 105.0% of control in vagina and 88.6% and 102.7% of control in clitoris at 4 and 8 Hz, respectively). These increases in genital blood flow were dependent on NO production as they were reduced upon intravenous administration of lmg/kg N-nitro-L-arginine methyl ester, an NO synthase inhibitor (37.1% and 48.5% of control in vagina; and 54.9% and 51.8% of control in clitoris at 4 and 8 Hz, respectively, p<0.01 vs. vehicle). Acute administration of paroxetine (5 mg/kg) also
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inhibited PNES-induced blood flow increases into vagina (39.0% and 43.3% of control at 4 and 8 Hz, respectively, p<0.01 vs. vehicle) and clitoris (52.5% and 53.1% of control at 4 and 8 Hz, respectively, p<0.01 vs. vehicle). Even at 1 mg/kg dose, paroxetine produced a significant impairment of blood flow responses to PNES (67.8% and 74.4% of control in vagina and 54.9% and 61.0% of control in clitoris at 4 and 8 Hz, respectively, p<0.05 vs. vehicle). Escitalopram (5 mg/kg) did not modify these responses in female rabbits (124.1% and 140.6% of control in vagina and 133.1% and 109.1% of control in clitoris at 4 and 8 Hz, respectively). The serotonin and norepinephrine reuptake inhibitor, venlafaxine (5 mg/kg), also produced a significant inhibition of blood flow in female rabbits (52.0% and 53.4% of control in vagina and 53.1% and 52.6% of control in clitoris at 4 and 8 Hz, respectively, p<0.01 vs. vehicle). The results show that paroxetine and venlafaxine, but not escitalopram, inhibit genital blood flow responses induced by PNES in the female rabbit. These results suggest that antidepressants may differ in their ability to cause sexual dysfunction in females and the underlying mechanisms are not shared by all the antidepressants/SSRIs.
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Mirtazapine versus paroxetine in elderly patients with anxious depression
M. Fava 1, W. Falk I , A. Schatzberg 2, C. Kremer 3, G. Murphy 2, H. Rodrigues 3. 1Massachusetts General Hospital, Boston,
Massachusetts, U.S.A.; 2Stanford University, Department of Psychiatry and Behavioral Sciences, Stanford, California, U.S.A.; 30rganon Pharmaceuticals Inc., Director, CNS, West Orange, New Jersey, U.S.A. Study Purpose: To evaluate in a double-blind, 8-week study the antidepressant efficacy and safety of mirtazapine (15-45 mg/day) compared with paroxetine (20-40 mg/day) in patients aged 65 or older with anxious major depressive disorder. Methods: Subjects were drawn from a larger sample of 255 outpatients 65 years of age or older participating in an 8-week, double blind study comparing the efficacy and safety of mirtazapine (15-45 mg/day) with paroxetine (20-40 mg/day). Eligible subjects met DSM IV criteria for major depression and were required to have a baseline HAM-D 17 score of 18 or higher and an age-adjusted Mini Mental State Examination (MMSE) score above the lowest 25th percentile. For the purpose of this study, we included in our analyses only patients who also met criteria for anxious depression (a HAM-D 17 anxiety/somatization score of 6 or higher). Assessments for efficacy and safety were obtained throughout the duration of the study (baseline, Day 7, 14, 21, 28, 42, and 56). Results: Mirtazapine-treated patients (n=86; women: 51.2%; mean age: 72.5 plus/minus 5.9) demonstrated comparable baseline demographics to patients receiving paroxetine (n=78; women: 51.3%; mean age: 71.5 plus/minus 4.7). Based on LOCF twoway ANOVA analyses, mirtazapine-treated patients experienced a significantly (p less than 0.05) greater reduction in depressive symptoms (assessed as either actual HAM-D 17 score or percent change in HAM-D 17 score from baseline) than paroxetine-treated patients at Days 7, 14, and 21, while the two treatment groups did not differ significantly at Days 28, 42, and 56. Remission rates (a HAM-D 17 score of 7 or less) were significantly (p less than 0.05) higher among mirtazapine-treated patients than among paroxetine-treated patients at Days 7 and 14 (5% vs. 0%, and 13% vs. 1%, respectively), but were not significantly different during