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P.1.120 Differential effects of chronic administration of fluvoxamine on serotonin in the rat hippocampus and raphe measured in vivo
P.1 Affective disorders and antidepressants
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Adjunctive long term treatment of therapy resistant circular psychoses with flupentixoldecanoat
E. Szabt, A. Erddlyi. "Jtsa Andrds'" County Hospital, Department of Psychiatry and psychotherapy, Nyiregyhtza, Hungary There is still little agreement about the treatment of therapy resistant circular psychoses. Sometimes a therapy is particularly unusual or potencially hazardous. The authors begun to treat 10 refractory circular caeses with combinations of carbamazepine and/or lithium and flupentixoldecanoat. The diagnoses were established according to the DSM-III R criteria. The 10 patient, who had severe circular psychosis (3-4 phases per year or one lasted longer than 6 months) and were treated initially with mood stabilizers without effect. The strategies of therapy was: (1) mood stabilizers/carbamazepine and/or Lithium; (2) mood stabilizers + antipsychotic(s) or antidepressant(s) + benzodiazepines; (3) ECT; (4) for long-term prolilaxis carbamazepine and/or Lithium and flupentixoldecanoat. The mean follow-up period was 30 months. An episode of hospitalisation is a good indicator of severity of relapse. There was a significant pozitiv relationship between the number and duration of hospitalisation episodes. The side effects were mild. Two patient whom had severe side effects we gave up the flupentixoldecanoat. Conclusion: Adjunctive long-term flupentixoldecanoat treatment in some cases can be usefull in refractory circular psychoses.
References A., J. Gelenberg, A. Frances, J., P. Docherty, D., A. Kahn: Treatment of bipolar Disorder J Clin Psychiatry 1996: 57/suppl 12/A/
~
Differential effects of chronic administration of fluvoxamine on serotonin in the rat hippocampus and raphe measured in vivo
O. Tajima, K. Nara, S. Nakada, S. Murata. Kyorin Universi~, School of Medicine, Department of Neuropsychiatry Tokyo, Japan Extracellular levels of serotonin (5-HT) and dopamine (DA) in the rat hippocampus and raphe nuclei were measured by using in vivo brain microdialysis in order to elucidate the underlying mechanisms of delayed onset of clinical action of selective serotonin reuptake inhibitors (SSRIs). Methods: Extracellular levels of 5-HT and DA in the hippocampus and raphe of male Wistar rats were measured by in vivo microdialysis with on-line high-performance liquid chromatography with electrochemical detection. Changes in 5-HT and DA were shown as percentages of baseline levels. Statistical analysis was done by using two-way analysis of variance (ANOVA). Results: Acute i.p. injection of fluvoxamine, 60 mg/kg showed differential effects on the extracellular levels of 5-HT in the hippocampus and raphe, transient two-fold increase and more continuous three-fold increases respectively. These differences in increase in 5-HT after acute administration of fluvoxamine were statistically significant. In contrast, Chronic administration of fluvoxamine (pretreatment of subcutaneous injection of fluvoxamine, 10 mg/kg for 14 days using osmotic minipump with additional i.p. Injection of fluvoxamine, 60 mg/kg at day 15th) showed dose-dependent increase in 5-HT in the hippocampus and these changes in 5-HT were siginificantly different from those after acute administration (significantly more persistent increase in 5-HT after chronic administration). On the other hand, Changes in 5-HT in the raphe following chronic fluvoxamine treatment were different from those in the hippocampus. Increase in 5-HT in the raphe was significantly attenuated following chronic fluvoxamine pretreatment compared to those after single administration and also saline control (pretreatment with saline for 14 days with additional i.p. fluvoxamine administration. Conclusion: These results were consistent with previous reports (Adell et al., 1991; lnvernizzi et al., 1992; Kreiss et al., 1994) and suggest that the attenuation of fluvoxamine-induced increase in 5-HT in the raphe following chronic administration may underlie the persistent increase in 5-HT in terminal area and may explain the delayed onset of action.
References [l] Adell, A., and F. Artigas, 1991, Naunyn-Schmiedberg'sArch. Pharmacol, 343, 237.
S173
[2] Invernizzi, R., Bellis, S., and R. Samanin, 1992, Brain research, 582, 322. [3] Kreiss, D.S., and I. Lucki, 1994, J. Pharmacol. Experimental. Therapeutics, 269, 1268.
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Pindolol addition shorten delay of action of paroxetine in major depression: A double blind controlled trial
P. Thomas, R. Bordet, J.Y. Alexandre, J. Catteau, C. Cyran, T. Danel, i. Debieve, J.E Dumon, E Dumont, D. Dutoit, D. Duthoit, C. Gerand, N. Lalaux, E Lanvin, E Lebert, J. Louvrier, J.E Maux, C. Plumecocq, 1t. Scottez, D. Servant, E. Trinh, G. Vaiva, J. Vignau, C.E Thomas, 1t. Dupuis. REPP: Reseau de Recherche et d'Experimentation
?sychopharmacologique; Unit~ d'~valuation du CHR& U de Lille; Service de Pharmacologie Hospitali~re; Lille, France Background: In Major depressive disorders, the delay of onset of antidepressant response remains a therapeutical issue. Recent open studies have suggested that this delay may be shortened when SSRl are associated with pindolol, a beta-adrenergic antagonist which also exhibits a 5HTla antagonist profile. Objective: A double blind placebo controlled, parallel design study was driven to compare the effect of pindolol to placebo in addition to paroxetine on the onset of response in patients with major depression. Methods: 112 Patients meeting DSM IV criteria of major depression with a score over 18 on the 17 item HDRS were recruited by 20 psychiatrists of the REPE They were all treated with paroxetthe (20 rag/day), randomly associated, for the first 21 days, with either pindolol (5 mg tid) or placebo. HDRS, MADRS and GCI were performed on DO, D5, D10, D15, D21, D25, D31. In order to test the hypothesis of an earlier onset of response in one of the group (paroxetine + pindolol versus paroxetine + placebo), the effect of l:time, 2: group and 3: time x group was assessed by a repeated measures multivariate analyses of variance based on HDRS MADRS and CGI values. Results: The analysis of the first month results of 100 patients (pindolol, n = 50); placebo, n = 50) was performed. There were no significant difference of socio-demographical and initial clinical features between groups. In "intent-to-treat" analysis, the number of recovered patients, defined as patients with a maximum score of 10 on the 17-item HDRS, was significantly higher at D 10 in the pindolol group; than in the placebo group (48% vs 26%; X2 = 5.2, df = 1, p < 0.03). At D5, there was not yet significant difference and at D15 and thereon, the differences hetween the 2 groups disappeared. Analysis of the 80 patients who had completed study until D31 showed that HDRS, MADRS and GCI scores were significantly lower on D5 and D 10 in the pindolol group. Conclusion: These results strongly suggest that the delay of action of antidepressant within patients suffering from major depression may be shorten with the addition of pindolol.
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Tolerability of mirtazapine in a naturalistic patient setting
L. Timmerman L 1, E. Vester E 2 . 1 Delta Psychiatric Hospital, Portugal:
'2NV Organon, Oss, The Netherlands Aim: To assess tolerability of mirtazapine (starting dose 15 or 30 mg/day; up to 60 mg/day) in an open-label, non-comparative, naturalistic study. Method: Patients in need of pharmacological treatment with antidepressants as assessed by psychiatrists or GPs in The Netherlands, were included in the study. Participating psychiatrists were working in different clinical settings, involving primary, outpatient and inpatient care. A spe,:ially developed check-lists in the Dutch language for global assessments of efficacy and tolerability were used in this study. The patients were :assessed at screening, and 1, 2 to 3 weeks and 3 months after beginning the treatment with mirtazapine. The investigators had the option either to start with mirtazapine 15 mg/day for 4 days, and tc, increase to 30 rag/day from day 5, or to start with 30 rag/day from day 1 onwards. The maximum prescribed dosage of mirtazapine was 60 mg/day. Results: A total of 596 patients were included in the study; 38 patients (7%) dropped out due to adverse events, and 1 patient (0.2%) due to adverse events combined with lack of efficacy. After tile first week of
•
Adjunctive long term treatment of therapy resistant circular psychoses with flupentixoldecanoat
E. Szabt, A. Erddlyi. "Jtsa Andrds'" County Hospital, Department of Psychiatry and psychotherapy, Nyiregyhtza, Hungary There is still little agreement about the treatment of therapy resistant circular psychoses. Sometimes a therapy is particularly unusual or potencially hazardous. The authors begun to treat 10 refractory circular caeses with combinations of carbamazepine and/or lithium and flupentixoldecanoat. The diagnoses were established according to the DSM-III R criteria. The 10 patient, who had severe circular psychosis (3-4 phases per year or one lasted longer than 6 months) and were treated initially with mood stabilizers without effect. The strategies of therapy was: (1) mood stabilizers/carbamazepine and/or Lithium; (2) mood stabilizers + antipsychotic(s) or antidepressant(s) + benzodiazepines; (3) ECT; (4) for long-term prolilaxis carbamazepine and/or Lithium and flupentixoldecanoat. The mean follow-up period was 30 months. An episode of hospitalisation is a good indicator of severity of relapse. There was a significant pozitiv relationship between the number and duration of hospitalisation episodes. The side effects were mild. Two patient whom had severe side effects we gave up the flupentixoldecanoat. Conclusion: Adjunctive long-term flupentixoldecanoat treatment in some cases can be usefull in refractory circular psychoses.
References A., J. Gelenberg, A. Frances, J., P. Docherty, D., A. Kahn: Treatment of bipolar Disorder J Clin Psychiatry 1996: 57/suppl 12/A/
~
Differential effects of chronic administration of fluvoxamine on serotonin in the rat hippocampus and raphe measured in vivo
O. Tajima, K. Nara, S. Nakada, S. Murata. Kyorin Universi~, School of Medicine, Department of Neuropsychiatry Tokyo, Japan Extracellular levels of serotonin (5-HT) and dopamine (DA) in the rat hippocampus and raphe nuclei were measured by using in vivo brain microdialysis in order to elucidate the underlying mechanisms of delayed onset of clinical action of selective serotonin reuptake inhibitors (SSRIs). Methods: Extracellular levels of 5-HT and DA in the hippocampus and raphe of male Wistar rats were measured by in vivo microdialysis with on-line high-performance liquid chromatography with electrochemical detection. Changes in 5-HT and DA were shown as percentages of baseline levels. Statistical analysis was done by using two-way analysis of variance (ANOVA). Results: Acute i.p. injection of fluvoxamine, 60 mg/kg showed differential effects on the extracellular levels of 5-HT in the hippocampus and raphe, transient two-fold increase and more continuous three-fold increases respectively. These differences in increase in 5-HT after acute administration of fluvoxamine were statistically significant. In contrast, Chronic administration of fluvoxamine (pretreatment of subcutaneous injection of fluvoxamine, 10 mg/kg for 14 days using osmotic minipump with additional i.p. Injection of fluvoxamine, 60 mg/kg at day 15th) showed dose-dependent increase in 5-HT in the hippocampus and these changes in 5-HT were siginificantly different from those after acute administration (significantly more persistent increase in 5-HT after chronic administration). On the other hand, Changes in 5-HT in the raphe following chronic fluvoxamine treatment were different from those in the hippocampus. Increase in 5-HT in the raphe was significantly attenuated following chronic fluvoxamine pretreatment compared to those after single administration and also saline control (pretreatment with saline for 14 days with additional i.p. fluvoxamine administration. Conclusion: These results were consistent with previous reports (Adell et al., 1991; lnvernizzi et al., 1992; Kreiss et al., 1994) and suggest that the attenuation of fluvoxamine-induced increase in 5-HT in the raphe following chronic administration may underlie the persistent increase in 5-HT in terminal area and may explain the delayed onset of action.
References [l] Adell, A., and F. Artigas, 1991, Naunyn-Schmiedberg'sArch. Pharmacol, 343, 237.
S173
[2] Invernizzi, R., Bellis, S., and R. Samanin, 1992, Brain research, 582, 322. [3] Kreiss, D.S., and I. Lucki, 1994, J. Pharmacol. Experimental. Therapeutics, 269, 1268.
[•
Pindolol addition shorten delay of action of paroxetine in major depression: A double blind controlled trial
P. Thomas, R. Bordet, J.Y. Alexandre, J. Catteau, C. Cyran, T. Danel, i. Debieve, J.E Dumon, E Dumont, D. Dutoit, D. Duthoit, C. Gerand, N. Lalaux, E Lanvin, E Lebert, J. Louvrier, J.E Maux, C. Plumecocq, 1t. Scottez, D. Servant, E. Trinh, G. Vaiva, J. Vignau, C.E Thomas, 1t. Dupuis. REPP: Reseau de Recherche et d'Experimentation
?sychopharmacologique; Unit~ d'~valuation du CHR& U de Lille; Service de Pharmacologie Hospitali~re; Lille, France Background: In Major depressive disorders, the delay of onset of antidepressant response remains a therapeutical issue. Recent open studies have suggested that this delay may be shortened when SSRl are associated with pindolol, a beta-adrenergic antagonist which also exhibits a 5HTla antagonist profile. Objective: A double blind placebo controlled, parallel design study was driven to compare the effect of pindolol to placebo in addition to paroxetine on the onset of response in patients with major depression. Methods: 112 Patients meeting DSM IV criteria of major depression with a score over 18 on the 17 item HDRS were recruited by 20 psychiatrists of the REPE They were all treated with paroxetthe (20 rag/day), randomly associated, for the first 21 days, with either pindolol (5 mg tid) or placebo. HDRS, MADRS and GCI were performed on DO, D5, D10, D15, D21, D25, D31. In order to test the hypothesis of an earlier onset of response in one of the group (paroxetine + pindolol versus paroxetine + placebo), the effect of l:time, 2: group and 3: time x group was assessed by a repeated measures multivariate analyses of variance based on HDRS MADRS and CGI values. Results: The analysis of the first month results of 100 patients (pindolol, n = 50); placebo, n = 50) was performed. There were no significant difference of socio-demographical and initial clinical features between groups. In "intent-to-treat" analysis, the number of recovered patients, defined as patients with a maximum score of 10 on the 17-item HDRS, was significantly higher at D 10 in the pindolol group; than in the placebo group (48% vs 26%; X2 = 5.2, df = 1, p < 0.03). At D5, there was not yet significant difference and at D15 and thereon, the differences hetween the 2 groups disappeared. Analysis of the 80 patients who had completed study until D31 showed that HDRS, MADRS and GCI scores were significantly lower on D5 and D 10 in the pindolol group. Conclusion: These results strongly suggest that the delay of action of antidepressant within patients suffering from major depression may be shorten with the addition of pindolol.
[•
Tolerability of mirtazapine in a naturalistic patient setting
L. Timmerman L 1, E. Vester E 2 . 1 Delta Psychiatric Hospital, Portugal:
'2NV Organon, Oss, The Netherlands Aim: To assess tolerability of mirtazapine (starting dose 15 or 30 mg/day; up to 60 mg/day) in an open-label, non-comparative, naturalistic study. Method: Patients in need of pharmacological treatment with antidepressants as assessed by psychiatrists or GPs in The Netherlands, were included in the study. Participating psychiatrists were working in different clinical settings, involving primary, outpatient and inpatient care. A spe,:ially developed check-lists in the Dutch language for global assessments of efficacy and tolerability were used in this study. The patients were :assessed at screening, and 1, 2 to 3 weeks and 3 months after beginning the treatment with mirtazapine. The investigators had the option either to start with mirtazapine 15 mg/day for 4 days, and tc, increase to 30 rag/day from day 5, or to start with 30 rag/day from day 1 onwards. The maximum prescribed dosage of mirtazapine was 60 mg/day. Results: A total of 596 patients were included in the study; 38 patients (7%) dropped out due to adverse events, and 1 patient (0.2%) due to adverse events combined with lack of efficacy. After tile first week of