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Clinical relevence of antibodies against serotonin and gangliosides, and acute phase proteins in major depression
P.l Affective disorders andantidepressants of anti-serotonin and anti-gangliosides antibodies, as well as the fact that gangliosides are components of serotonin receptors could prompt us to speculatethat they may be anti-receptor antibodies. The results obtained may suggest that autoimmune disorder is involved in pathogenesis of fibromyalgia and major depression. References [1] KleinR.• BanschM.• BergP A. (1992)Clinical relevance of antibodies against serotonin and gangliosides in patients with primary tibromyalgia syndrome. Psychoneuroendocrinology. 17,6: 593-598 . [2] Samborski W., T. Stratz., A. Sluzewska et al, (1996) Neuromodulatoren in der Differential diagnose Fibromyalgia-Depression. Act. Rhematol. (in press).
IP.1.0421 Clinical relevence of antibodies against serotonin andgangllosldes, and acute phase proteins in major depression
A. Sluzewska J, W. Samborski2, M. Sobieska2. R. Klein 3. J Department of Adult Psychiatry, University of Medical Sciences in Poznan. Poland; 2 Department of Immunology and Rheumatology, University of Medical Sciences in Poznan, Poland; 3 Department of Internal Medicine, UniversityofTubingen. Germany There is strongevidencethat majordepression is accompanied by an acute phase response, characterized by elevated levels of positive acute phase proteins (apps) and decreased levels of negative apps. Moreover several authors showed the occurrence of antinuclear and antiphospholipid and antiserotonin antibodiesin depression. This study has been conducted in order to investigate if depressed patients with acute phase response are characterized by presence of antibodies against serotonin and gangliosides. We have measured serum antibodyreactivity of the IgG and IgM type to serotonin and gangliosides as well as three apps: C-reactive protein(CRP), alpha-l-acid glycoprotein (AGP) and alpha-l-antychymotrypsin (ACf ) and major microheterogeneity of AGP and ACf in 20 inpatients (16 women and 4 men) from Department of Adult Psychiatry in Poznan and in 25 normal controls. Diagnosiswas assessedaccording to DSM IV and lCD-Criteriaas Major Depressive Disorder, Recurentn =10and BipolarDisordern =10.All patients were medicallyhealthy, they had normal values of blood and urine tests. Mean age of patientswas 42.3 (SD ± 12.5). They weredrug free for at least 7 days before blood sampling. Serum concentration of antibodies and apps as wellas clinicalstatus(HDRS-17 item) wereperformed before treatment. A standart ELISA technique was used for antibody detection. Antigent used in ELISA: for serotonin (5-HT) was obtain from Sigma (St. Louis MO, USA),for gangliosides (Gml, GDla, GDlb, GTlb ) from Boehringer (Mannheim, Germany). Concentration of apps was mesured by rocket immunoelectrophoresis and reactivity coefficient (RC) of their microheterogeneity by cross-affinity immunoelectrophoressis with free Con A as a ligand. Patientswith majordepressionshoweda significant antibody reactivity to serotonin in 11 out of 20 patients (55%) and to gangliosides in 10out of 20 patients (50%) patients.In controls presenceof these antigens was6% and 13% respectively. Mean values of CRP, AGP and ACf in depresed patients were: 1.35 ± 0.6 mgIJ, 1240 ± 304 mgIJ, 487 mgIJ respecively. The value of AGP-RC was 1.4 ± 0.3 and of ACf-RC was 4.3 ± 1.3. Patients with presence of antibodies against serotonin and gangliosides had moreelevated levelsof AGP(1345 ± 320 mgIJ) and ACT(532 ± 170 mg/l) than those whithout antibodies AGP (1105 ± 340 mgIJ) and ACT (425 ± 150 mg/l). They had also differentpaternsof rnicroheterogeneity with higher values of AGP·RC (1.5 ± 0.4) vs (1.2 ± 0.3) in patients without antibodies. Eight of eleven (73%) depressed patients with antibodies against serotonin and gangliosides were treatment resistant in the depressed episodestudied.In the furtherevaluation they failedto respond to two adequatantidepressant trials and needed the augmentation therapy with lithium or carbamazpine. These results could point to a role of antibodies against seotonin and gangliosides (which may represent component of serotonin receptor) in acute phaseresponseobservedin depression, which is specialy evident in refractory depression.
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IP.1.0431 Toxicity ofantidepressant drugs: A comparative in vitro study S. Lisch, F. Holsboer, C. Behl. MaxPlanckInstitute of Psychiatry, Clinical Institute, Kraepelinstr; 10, 80804 Munich, Germany Tricyclic antidepressants affect different receptor systems and therefore may lead to a variety of adverse effects. Recently. more selective antidepressants such as moclobernide, a reversible monoamine oxidase-A (MAO-A) inhibitor and the selective serotoninreuptake inhibitors paroxe~e: ~uvoxarnine andfluoxetine have beendeveloped. To studypotential toxicities of these three classes of antidepressants we investigated the effect of amitriptyline, maprotiline, paroxetine, fluoxetine, fluvoxamine and moclobemide on the survival of four different cell lines. Clonal hippocampal cells (HT22, HNIO), 3T3 fibroblasts and kidney SV40 transformed monkey cells (COS) were incubated with antidepressants up to 10-4 M for 24, 48 and 72 hours. Viability assays which measure the ~duction of 3-(4,5-dimethylthiazol-2-yl)-2.5 diphenyl tetrazolium bromide(MTT)to a coloredformazan were used to assess cell survival. The tricyclic antidepressants amitriptyline and maprotiline led to a significant decrease in MTT reduction after a 24-hour incubation at 50 JLM. After 72 hours almost all cells were lysed. Lower concentrations of these tricyclic antidepressants were non-toxic. A similar effect was detected after incubation with paroxetine and fluoxetine at the same ~ncentration. Fluvoxamine induceda decreasedcell viabilityof approximately 50% after 24 hours and 25% after 72 hours of incubation. The only antidepressant that did not induce a toxic effect in any cell line even at 10- 4 M was the reversible MAD-Ainhibitormoclobemide.
I P.1.044I Effects of selective serotonin reuptake inhibitors given repeatedly on 5-HT receptor sUbpopulatlons in theratbrain J. Maj, M. Dziedzicka-Wasylewska, V. Klimek, E. Moryl, Z. Rogoz, G. Skuza. Institute of Pharmacology. Polish Academyof Sciences, 12 Smetna St., PI31-343 Krakow; Poland
Effects of selective serotonin reuptake inhibitors on the rat brain were evaluated pharmacologically and biochemically. Male Wistar rats were used. Paroxetine, citalopram and fluoxetine were given in a dose of 10 mglkg p.o.• twice daily, for 14 days. For comparison. the drugs were administered acutely (10 mglkg p.o.). Paroxetine given repeatedly (but not acutely) antagonized the 8OH·DPAT-induced behavioural syndrome(a 5-HTIA effect). Citalopram and fluoxetine were inactive. The exploratory hypoactivity evoked by m-chlorophenylpiperazine (a 5-HT1c/5-HT2C effect) was reduced by repeated paroxetine, citalopram and f1uoxetine. When givenacutely, all the serotonin reuptake inhibitors studied enhanced the 5-HTP-induced head twitches (a 5-HT2A effect), but inhibited them after repeated treatment. The ,hyperthermia induced by trifluoromethylphenylpiperazine at a high amblen~ temperature (a 5-HT2A effect) was antagonized by repeated paroxetme, citalopram and f1uoxetine. Biochemical studies demonstrated that repeated paroxetine decreased the density of and increased the affinity for 5·HT 1A receptors in the hippocampus (rJH]-8-0H.DPAT as a ligand). Citalopram increased the density of 5-HTIA receptors and did not change the affinity for them. Fluoxetine affected neither the density nor the affinity. The density of 5-HT2A receptors «(3H]-ketanserin as a ligand). measured in the cortex. was decreased after repeated paroxetine and citalopram, whereas the affinity was not changed. Repeated f1uoxetine was able to increase the density of 5·HT2A receptors, but it did not affect the affinity. The obtained resultsindicate that the three selective serotoninreuptake inhibitors given repeatedly induce secondary changes in 5-HT2A receptors. which lead to reduction of the 5-HT2 neurotransmission (reduced responsiveness of 5-HT2A postsynaptic receptorsto their agonists). There is no close parallel betweenpharmacological and biochemical results.All the serotonin reuptake inhibitors tested also decrease the responsiveness of 5-HT1cl5-HT2C postsynaptic receptors. There are differences between the drugs studied in respect of their effectson 5HTI Areceptors.
IP.1.0421 Clinical relevence of antibodies against serotonin andgangllosldes, and acute phase proteins in major depression
A. Sluzewska J, W. Samborski2, M. Sobieska2. R. Klein 3. J Department of Adult Psychiatry, University of Medical Sciences in Poznan. Poland; 2 Department of Immunology and Rheumatology, University of Medical Sciences in Poznan, Poland; 3 Department of Internal Medicine, UniversityofTubingen. Germany There is strongevidencethat majordepression is accompanied by an acute phase response, characterized by elevated levels of positive acute phase proteins (apps) and decreased levels of negative apps. Moreover several authors showed the occurrence of antinuclear and antiphospholipid and antiserotonin antibodiesin depression. This study has been conducted in order to investigate if depressed patients with acute phase response are characterized by presence of antibodies against serotonin and gangliosides. We have measured serum antibodyreactivity of the IgG and IgM type to serotonin and gangliosides as well as three apps: C-reactive protein(CRP), alpha-l-acid glycoprotein (AGP) and alpha-l-antychymotrypsin (ACf ) and major microheterogeneity of AGP and ACf in 20 inpatients (16 women and 4 men) from Department of Adult Psychiatry in Poznan and in 25 normal controls. Diagnosiswas assessedaccording to DSM IV and lCD-Criteriaas Major Depressive Disorder, Recurentn =10and BipolarDisordern =10.All patients were medicallyhealthy, they had normal values of blood and urine tests. Mean age of patientswas 42.3 (SD ± 12.5). They weredrug free for at least 7 days before blood sampling. Serum concentration of antibodies and apps as wellas clinicalstatus(HDRS-17 item) wereperformed before treatment. A standart ELISA technique was used for antibody detection. Antigent used in ELISA: for serotonin (5-HT) was obtain from Sigma (St. Louis MO, USA),for gangliosides (Gml, GDla, GDlb, GTlb ) from Boehringer (Mannheim, Germany). Concentration of apps was mesured by rocket immunoelectrophoresis and reactivity coefficient (RC) of their microheterogeneity by cross-affinity immunoelectrophoressis with free Con A as a ligand. Patientswith majordepressionshoweda significant antibody reactivity to serotonin in 11 out of 20 patients (55%) and to gangliosides in 10out of 20 patients (50%) patients.In controls presenceof these antigens was6% and 13% respectively. Mean values of CRP, AGP and ACf in depresed patients were: 1.35 ± 0.6 mgIJ, 1240 ± 304 mgIJ, 487 mgIJ respecively. The value of AGP-RC was 1.4 ± 0.3 and of ACf-RC was 4.3 ± 1.3. Patients with presence of antibodies against serotonin and gangliosides had moreelevated levelsof AGP(1345 ± 320 mgIJ) and ACT(532 ± 170 mg/l) than those whithout antibodies AGP (1105 ± 340 mgIJ) and ACT (425 ± 150 mg/l). They had also differentpaternsof rnicroheterogeneity with higher values of AGP·RC (1.5 ± 0.4) vs (1.2 ± 0.3) in patients without antibodies. Eight of eleven (73%) depressed patients with antibodies against serotonin and gangliosides were treatment resistant in the depressed episodestudied.In the furtherevaluation they failedto respond to two adequatantidepressant trials and needed the augmentation therapy with lithium or carbamazpine. These results could point to a role of antibodies against seotonin and gangliosides (which may represent component of serotonin receptor) in acute phaseresponseobservedin depression, which is specialy evident in refractory depression.
S4-75
IP.1.0431 Toxicity ofantidepressant drugs: A comparative in vitro study S. Lisch, F. Holsboer, C. Behl. MaxPlanckInstitute of Psychiatry, Clinical Institute, Kraepelinstr; 10, 80804 Munich, Germany Tricyclic antidepressants affect different receptor systems and therefore may lead to a variety of adverse effects. Recently. more selective antidepressants such as moclobernide, a reversible monoamine oxidase-A (MAO-A) inhibitor and the selective serotoninreuptake inhibitors paroxe~e: ~uvoxarnine andfluoxetine have beendeveloped. To studypotential toxicities of these three classes of antidepressants we investigated the effect of amitriptyline, maprotiline, paroxetine, fluoxetine, fluvoxamine and moclobemide on the survival of four different cell lines. Clonal hippocampal cells (HT22, HNIO), 3T3 fibroblasts and kidney SV40 transformed monkey cells (COS) were incubated with antidepressants up to 10-4 M for 24, 48 and 72 hours. Viability assays which measure the ~duction of 3-(4,5-dimethylthiazol-2-yl)-2.5 diphenyl tetrazolium bromide(MTT)to a coloredformazan were used to assess cell survival. The tricyclic antidepressants amitriptyline and maprotiline led to a significant decrease in MTT reduction after a 24-hour incubation at 50 JLM. After 72 hours almost all cells were lysed. Lower concentrations of these tricyclic antidepressants were non-toxic. A similar effect was detected after incubation with paroxetine and fluoxetine at the same ~ncentration. Fluvoxamine induceda decreasedcell viabilityof approximately 50% after 24 hours and 25% after 72 hours of incubation. The only antidepressant that did not induce a toxic effect in any cell line even at 10- 4 M was the reversible MAD-Ainhibitormoclobemide.
I P.1.044I Effects of selective serotonin reuptake inhibitors given repeatedly on 5-HT receptor sUbpopulatlons in theratbrain J. Maj, M. Dziedzicka-Wasylewska, V. Klimek, E. Moryl, Z. Rogoz, G. Skuza. Institute of Pharmacology. Polish Academyof Sciences, 12 Smetna St., PI31-343 Krakow; Poland
Effects of selective serotonin reuptake inhibitors on the rat brain were evaluated pharmacologically and biochemically. Male Wistar rats were used. Paroxetine, citalopram and fluoxetine were given in a dose of 10 mglkg p.o.• twice daily, for 14 days. For comparison. the drugs were administered acutely (10 mglkg p.o.). Paroxetine given repeatedly (but not acutely) antagonized the 8OH·DPAT-induced behavioural syndrome(a 5-HTIA effect). Citalopram and fluoxetine were inactive. The exploratory hypoactivity evoked by m-chlorophenylpiperazine (a 5-HT1c/5-HT2C effect) was reduced by repeated paroxetine, citalopram and f1uoxetine. When givenacutely, all the serotonin reuptake inhibitors studied enhanced the 5-HTP-induced head twitches (a 5-HT2A effect), but inhibited them after repeated treatment. The ,hyperthermia induced by trifluoromethylphenylpiperazine at a high amblen~ temperature (a 5-HT2A effect) was antagonized by repeated paroxetme, citalopram and f1uoxetine. Biochemical studies demonstrated that repeated paroxetine decreased the density of and increased the affinity for 5·HT 1A receptors in the hippocampus (rJH]-8-0H.DPAT as a ligand). Citalopram increased the density of 5-HTIA receptors and did not change the affinity for them. Fluoxetine affected neither the density nor the affinity. The density of 5-HT2A receptors «(3H]-ketanserin as a ligand). measured in the cortex. was decreased after repeated paroxetine and citalopram, whereas the affinity was not changed. Repeated f1uoxetine was able to increase the density of 5·HT2A receptors, but it did not affect the affinity. The obtained resultsindicate that the three selective serotoninreuptake inhibitors given repeatedly induce secondary changes in 5-HT2A receptors. which lead to reduction of the 5-HT2 neurotransmission (reduced responsiveness of 5-HT2A postsynaptic receptorsto their agonists). There is no close parallel betweenpharmacological and biochemical results.All the serotonin reuptake inhibitors tested also decrease the responsiveness of 5-HT1cl5-HT2C postsynaptic receptors. There are differences between the drugs studied in respect of their effectson 5HTI Areceptors.