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P.1.173 In vivo studies on the brain serotonin output in experimental chronic hepatic encephalopathy
P.1 Affective disorders and antidepressants
$190
effects were noted only in single cases. The duration of depressive states in the patients who rejected pharmacotherapy was significantly longer in contrast to patients receiving antidepressants. The social adjustment in the group under pharmacotherapy was higher (Table). Social adjustmentindes Remained job Continued study Family disturbances Delinquency Resumed drug use
Number of patients 21 (1 group) 11 (2 group) 8 2 7 I 4 6 1 5 7 8
Reliability P < 0.05 P < 0.05 P < 0.01 P < 0.002 P < 0.05
Conclusion: treatment of youth depressions with "mild" antidepressants is highly efficient and well tolerated, does not disturb the everyday activities and is a significant measure in preventing drug addictions and improving social adjustment of young people.
References [1] Bengtsson F., Bugge M., and Nobin A. (1989) Hepatncerebral dysfunction and brain serotonin. In: Bunerworth, R.E and Pomier I_,ayrargues,G. (Eds.), Hepatic Encephalopathy: Pathophysiology and Treatment. The Humana Press, Inc,. Clifton, NJ, pp. 355-387. [2] Bergqvist EB.E, Vngels B.A.EM., Bosman D.K., Maas M.A.W., Hjorth S.. Chamuleau R.A.EM., and Bengtsson E (1995) Neocortical diatysate monoamines of rats after acute, subacute, and chronic liver shunt. J. Neurochem. 64, 1238-1244. [3] Bergq~ist EB.E, Hjorth S., Audet R,, Apelqvist G., Bengtsson E, and Butterworth R.E (19%) Ammonium acetate challenge in experimental hepatic encephalopathy induces a transient increase of brain 5-HT release in vivo. Eu~ Neuropsychopharmacology 6, 317-322.
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Multidimensional assessment of suicidal patients, The relationship between biochemical, psychological and psychopathological factors
B. Ahrens 1, C. Schumann 1,3, H. Berzewski 1, A. BerghOfer 1, L. Franke 2, B. Mtiller-Oerlinghausen 1, R. Uebelhack ~. 1Psychiatrische
~ l n
vivo studies on the brain serotonin output in experimental chronic hepatic encephalopathy
P.B.F. Bergqvist, S. Hjorth 1, C. Wikell, G. Apelqvist, F. Bengtsson.
Depts of Clinical Pharmacology, Lund University, Lund; 1Pharmacology, University of Gothenburg, Gothenburg, Sweden Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that frequently will be observed in patients with chronic liver failure. The more precise pathogenesis of HE is, however, not known. In chronic experimental HE (studied as permanent surgical portacaval shunt in rats; PCS) an increased brain turnover of serotonin (5-hydroxytryptamine; 5-HT) as well as behavioral disturbances have been demonstrated (1). However, in the same chronic HE model, the extracellular neocortical 5-HT levels remain unaltered, possibly indicating unchanged brain 5-HT release despite a profoundly increased brain 5-HT metabolism (2). The possibility still remains that the neuronal 5-HT release pattern may be altered in chronic HE, but that this may have escaped detection under the experimental conditions applied in previous studies. If pharmacologically provoked (e.g. a coma-inducing ammonium acetate injection to PCS rats), a transient increase in the output of 5-HT has indeed been shown to follow (3). Aim: The present microdialysis study comprised two separate sets of experiments. In the first set, the KCl-evoked frontal neocortical output of 5-HT was studied in chronic PCS and sham-operated rats. In the second set, the neocortical output of 5-HT was monitored in PCS and control rats during local administration of p-chloroamphetamine (pCA) and d-fenfluramine (dFEN), two specific 5-HT releasing agents. Results: In the first experimental set, three consecutively repeated KCIperfusion pulses (60 raM) produced marked and reproducible increases (p < 0.01 versus corresponding baseline) in the 5-HT output in both PCS and sham-operated rats. Interestingly, the KCI challenge resulted in a more pronounced elevation of the 5-HT output in PCS as compared to sham rats (p < 0.05). In Ca 2+ -tree medium, the difference between PCS and control rats in the KCl-evoked release of 5-HT was abolished. In the second experimental series, local perfusion with pCA or dFEN (5 /zM; either agent) produced marked increases (0.05 > p > 0.001) in brain 5-HT release compared with corresponding baseline values, both in PCS and sham-operated rats, Whereas no difference in the dFEN-induced 5-HT response was seen between PCS and control rats, the effect of pCA perfusion upon the 5-HT output was clearly more marked (p < 0.05) in the PCS than in the sham group. Conclusions: These findings can be interpreted as if in experimental chronic HE, there is a potential for accentuated output of 5-HT from nerve terminals of the neocortex. A surplus of neuronal 5-HT (in HE) may, under ceKain pharmaco- and/or physiological conditions, be released into the synaptic cleft, in turn increasing the serotonergic tone. From a clinical perspective, this observation may warrant some caution regarding the use of, e.g., novel 5-HT-enhancing thymoleptics in liver impaired subjects. Further studies on the more precise pharmacodynamical effects of such drugs on the CNS 5-HT systems in chronic HE are clearly needed, not least from a drug safety point of view.
Klinik und Poliklinik der Freien Universitdt Berlin; 2 Universitdtsklinik und Poliklinik fiir Psychiatrie, Fakultiit der Humboldt-Universiti2t, Berlin; 3 Universitgitsklinik fiir Psvchiatrie Wien, Germany Suicidal behaviour as a multidimensional condition requires measurements made at levels of biochemical, psychological and psychopathological/behavioural factors. 30 inpatients admitted as a result of a suicide attempt to a psychiatric emergency unit were investigated (a) biochemically for peripheral serotonin parameters like 5HT uptake in platelets and blood concentration of serotonin, (b) psychologically for conformity with specific concepts of aggression, impulsivity and anger control and (c) psychopathologically/behaviourally for severity of depressive symptoms (HAMD, MADRS), an overall psychopathology (BPRS) diagnostic criteria and the distinction of suicidal behaviour into violent vs. non violent methods of self-destruction. More than 50% of the patients with a suicide attempt displayed reduced 5HT uptake and/or 5HT blood concentration. The whole group studied bad marked increased level of self-directed aggression and low levels of reactive aggression measured by FAF (German adaptation of Buss-Durkee Hostility Inventory). No difference was found in depressive symptoms measured with the MADRS and HAMD. Significantly more patients with violent suicidal behaviour had reduced serotonin parameters. The same distinction was found for those patients with suicide attempts in their history. The advantage of a simultaneous assessment of relevant factors of suicidality lies in the fact that it permits an examination of the interaction between psychological, behavioural and biochemical dimensions.
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A simple method for routine tdm of the novel antidepressant nefazodone and its main metabolite mCPP in serum by HPLC
Hemik Bjrrk, Finn Bengtsson. Department ~fClinical Pharmacology,
Lurid University Hospital, S-221 85 Lund, Sweden Introduction: Nefazodone (Nefadar®; NEF) is a novel antidepressant mainly me,tabolised in humans via CYP3A4 to the active metabolites hydroxynefazodone (OH-NEF) and triazolodidione, but also via CYP2D6 to the active metabolite m-chlorophenylpiperazine (mCPP). The pharmacologically active moities NEF and mCPP will occur in significant amounts in the blood under steady-state conditions in patients medicating orally with Nefadar ® and were chosen for development of a Therapeutic Drug Monitoring (TDM) routine. Methods: The compounds were extracted from 1.0 mL patient serum using a 1.0 mL Isolute HCX (130 mg) mixed bed solid phase extraction column. These analytes and the internal standards buspirone (BUS) and 1-PP were well separated within 10 min on a Sphersorb cyanopropyl 150 x 4 mm analytical column. Mobile phase (flow 1.5 mL/min) comprised of acetonitrile-10 mM phosphate buffer (50/50; pH 6.5). This HPLC-system were connected to a UV-detector working at 254 nm.
$190
effects were noted only in single cases. The duration of depressive states in the patients who rejected pharmacotherapy was significantly longer in contrast to patients receiving antidepressants. The social adjustment in the group under pharmacotherapy was higher (Table). Social adjustmentindes Remained job Continued study Family disturbances Delinquency Resumed drug use
Number of patients 21 (1 group) 11 (2 group) 8 2 7 I 4 6 1 5 7 8
Reliability P < 0.05 P < 0.05 P < 0.01 P < 0.002 P < 0.05
Conclusion: treatment of youth depressions with "mild" antidepressants is highly efficient and well tolerated, does not disturb the everyday activities and is a significant measure in preventing drug addictions and improving social adjustment of young people.
References [1] Bengtsson F., Bugge M., and Nobin A. (1989) Hepatncerebral dysfunction and brain serotonin. In: Bunerworth, R.E and Pomier I_,ayrargues,G. (Eds.), Hepatic Encephalopathy: Pathophysiology and Treatment. The Humana Press, Inc,. Clifton, NJ, pp. 355-387. [2] Bergqvist EB.E, Vngels B.A.EM., Bosman D.K., Maas M.A.W., Hjorth S.. Chamuleau R.A.EM., and Bengtsson E (1995) Neocortical diatysate monoamines of rats after acute, subacute, and chronic liver shunt. J. Neurochem. 64, 1238-1244. [3] Bergq~ist EB.E, Hjorth S., Audet R,, Apelqvist G., Bengtsson E, and Butterworth R.E (19%) Ammonium acetate challenge in experimental hepatic encephalopathy induces a transient increase of brain 5-HT release in vivo. Eu~ Neuropsychopharmacology 6, 317-322.
•
Multidimensional assessment of suicidal patients, The relationship between biochemical, psychological and psychopathological factors
B. Ahrens 1, C. Schumann 1,3, H. Berzewski 1, A. BerghOfer 1, L. Franke 2, B. Mtiller-Oerlinghausen 1, R. Uebelhack ~. 1Psychiatrische
~ l n
vivo studies on the brain serotonin output in experimental chronic hepatic encephalopathy
P.B.F. Bergqvist, S. Hjorth 1, C. Wikell, G. Apelqvist, F. Bengtsson.
Depts of Clinical Pharmacology, Lund University, Lund; 1Pharmacology, University of Gothenburg, Gothenburg, Sweden Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that frequently will be observed in patients with chronic liver failure. The more precise pathogenesis of HE is, however, not known. In chronic experimental HE (studied as permanent surgical portacaval shunt in rats; PCS) an increased brain turnover of serotonin (5-hydroxytryptamine; 5-HT) as well as behavioral disturbances have been demonstrated (1). However, in the same chronic HE model, the extracellular neocortical 5-HT levels remain unaltered, possibly indicating unchanged brain 5-HT release despite a profoundly increased brain 5-HT metabolism (2). The possibility still remains that the neuronal 5-HT release pattern may be altered in chronic HE, but that this may have escaped detection under the experimental conditions applied in previous studies. If pharmacologically provoked (e.g. a coma-inducing ammonium acetate injection to PCS rats), a transient increase in the output of 5-HT has indeed been shown to follow (3). Aim: The present microdialysis study comprised two separate sets of experiments. In the first set, the KCl-evoked frontal neocortical output of 5-HT was studied in chronic PCS and sham-operated rats. In the second set, the neocortical output of 5-HT was monitored in PCS and control rats during local administration of p-chloroamphetamine (pCA) and d-fenfluramine (dFEN), two specific 5-HT releasing agents. Results: In the first experimental set, three consecutively repeated KCIperfusion pulses (60 raM) produced marked and reproducible increases (p < 0.01 versus corresponding baseline) in the 5-HT output in both PCS and sham-operated rats. Interestingly, the KCI challenge resulted in a more pronounced elevation of the 5-HT output in PCS as compared to sham rats (p < 0.05). In Ca 2+ -tree medium, the difference between PCS and control rats in the KCl-evoked release of 5-HT was abolished. In the second experimental series, local perfusion with pCA or dFEN (5 /zM; either agent) produced marked increases (0.05 > p > 0.001) in brain 5-HT release compared with corresponding baseline values, both in PCS and sham-operated rats, Whereas no difference in the dFEN-induced 5-HT response was seen between PCS and control rats, the effect of pCA perfusion upon the 5-HT output was clearly more marked (p < 0.05) in the PCS than in the sham group. Conclusions: These findings can be interpreted as if in experimental chronic HE, there is a potential for accentuated output of 5-HT from nerve terminals of the neocortex. A surplus of neuronal 5-HT (in HE) may, under ceKain pharmaco- and/or physiological conditions, be released into the synaptic cleft, in turn increasing the serotonergic tone. From a clinical perspective, this observation may warrant some caution regarding the use of, e.g., novel 5-HT-enhancing thymoleptics in liver impaired subjects. Further studies on the more precise pharmacodynamical effects of such drugs on the CNS 5-HT systems in chronic HE are clearly needed, not least from a drug safety point of view.
Klinik und Poliklinik der Freien Universitdt Berlin; 2 Universitdtsklinik und Poliklinik fiir Psychiatrie, Fakultiit der Humboldt-Universiti2t, Berlin; 3 Universitgitsklinik fiir Psvchiatrie Wien, Germany Suicidal behaviour as a multidimensional condition requires measurements made at levels of biochemical, psychological and psychopathological/behavioural factors. 30 inpatients admitted as a result of a suicide attempt to a psychiatric emergency unit were investigated (a) biochemically for peripheral serotonin parameters like 5HT uptake in platelets and blood concentration of serotonin, (b) psychologically for conformity with specific concepts of aggression, impulsivity and anger control and (c) psychopathologically/behaviourally for severity of depressive symptoms (HAMD, MADRS), an overall psychopathology (BPRS) diagnostic criteria and the distinction of suicidal behaviour into violent vs. non violent methods of self-destruction. More than 50% of the patients with a suicide attempt displayed reduced 5HT uptake and/or 5HT blood concentration. The whole group studied bad marked increased level of self-directed aggression and low levels of reactive aggression measured by FAF (German adaptation of Buss-Durkee Hostility Inventory). No difference was found in depressive symptoms measured with the MADRS and HAMD. Significantly more patients with violent suicidal behaviour had reduced serotonin parameters. The same distinction was found for those patients with suicide attempts in their history. The advantage of a simultaneous assessment of relevant factors of suicidality lies in the fact that it permits an examination of the interaction between psychological, behavioural and biochemical dimensions.
•1
A simple method for routine tdm of the novel antidepressant nefazodone and its main metabolite mCPP in serum by HPLC
Hemik Bjrrk, Finn Bengtsson. Department ~fClinical Pharmacology,
Lurid University Hospital, S-221 85 Lund, Sweden Introduction: Nefazodone (Nefadar®; NEF) is a novel antidepressant mainly me,tabolised in humans via CYP3A4 to the active metabolites hydroxynefazodone (OH-NEF) and triazolodidione, but also via CYP2D6 to the active metabolite m-chlorophenylpiperazine (mCPP). The pharmacologically active moities NEF and mCPP will occur in significant amounts in the blood under steady-state conditions in patients medicating orally with Nefadar ® and were chosen for development of a Therapeutic Drug Monitoring (TDM) routine. Methods: The compounds were extracted from 1.0 mL patient serum using a 1.0 mL Isolute HCX (130 mg) mixed bed solid phase extraction column. These analytes and the internal standards buspirone (BUS) and 1-PP were well separated within 10 min on a Sphersorb cyanopropyl 150 x 4 mm analytical column. Mobile phase (flow 1.5 mL/min) comprised of acetonitrile-10 mM phosphate buffer (50/50; pH 6.5). This HPLC-system were connected to a UV-detector working at 254 nm.