- Email: [email protected]
P.2.060 The efficacy of risperidone in the managementof attempted suicide in patients with schizophrenia
P2, _PsyoBotio disorders and a~tipsye#otics
S258
habenula, or a sham procedure, were per%rmed. After a recovery period of one wee}: behavioural testing was re-initiated. The lesion caused a pronounced and long-lasting enhancement of the mean number of premature responses (significant effects of group [F(1,14)=9.9, p<0.007] and of day [F(11,154)=7.3, p<0.0001]). Additionally, by three to four weeks post-surgery, lesioned animals showed a significant decrease of choice accuracy measured by percent correct responses, t-laloperidol (0.03 mg/kg) significantly reduced the number of premature responses in lesioned and sham animals (significant effects of group [F(1,14)=8.8, p=0.01], treatment [F(2,28)=4.4, p=0.022] and no significant interaction [F(2,28)=1.1, p>0.1]). In contrast, haloperidol did not influence choice accuracy. Amphetamine increased premature responses in lesioned and sham animals without affecting choice accuracy. The effects of haloperidol and amphetamine suggest that increased premature responses may be due to acute dopaminergic hyperactivity, whereas decreased choice accuracy is a progressive deficit not attributable to such an acute effect. As increased premature responses have been attributed to either a decrease of serotonin or increase of dopamine activity, and considering that the habenula participates in the regulation of mesolimbic, mesostriatal and mesocortical monoaminergio paths (Lisoprawski etal., 1980), the results are consistent with the view that pathology of the habenula contributes to the cognitive impairments of schizophrenia by two mechanisms, first by disturbing midbrain to forebrain monoaminergic neurotransmission, and secondly by a non-dopaminergic progressive process (e.g Kelly, 1998).
References Lisoprawsld A., Herve D., Blanc G., Glowinski J. & Tassin J.R, 1980. Selective activation of the mesocortieo-frontal dopaminergie n~rons induced by lesion of the habenula in the rat. Brain Researdl. 183, 22%234. Kelly, P.H., 1998. Defective inhibition of dream-e~ents memory formation: a hypothesized mechanism in the onset and progression of symptoms of s&izcphremia. Brain Res Bull. 46, 18%97.
•
Catechol-O-methyltran sferase gene polymorphism in symptomatology of schizophrenia
C .T. Lee-.,H.K. Lee, Y.S. Kwon, K.U. Lee. :T~e Cat/~olic U-nioersity
of Korea, Departmem of Psycfgatry, Department of Psychiatry, Uijongbu city, Republic of Korea Pm'l~OSe-" Catechol-O-Methyltranferase (C©MT) gene is involved dopamine metabolism, which has been implicated to have putative role in the pathogenesis schizophrenia and aggressive behaviors. Although evidence exists for an association between aggression and schizophrenia, the pathogenesis of aggression in schizophrenia has not been established. We carried out this study to evaluate the association between schizophrenia, its psychopathologics (positive symptom, negative symptom, aggression) and COMT gone polymorphism. lVleth~l: One hundred and twenty four patients with schizophrenia by DSM-III who admitted to Uijongbu St. May's hospotal and 94 normal controls were participated in this study. The evaluation of patients was accomplished by positive & negative syndrome scale (PANSS) and overt aggression scale (OAS). The analysis of COMT gone polymosphism was perfomed using PCR method with RFLR ResuR: There was no statistically significant differences between frequencies of COMT genotype in patients and controls.
Although the average of positive & negative subscale of PANSS and OAS were not significantly different between the COMT variants, there was tendency that patients with COMT L/L have higher negative subscale of PANSS than other group. Conclusion: This result suggests that COMT gone polymorphism was not associated with development and syrrptomatology of schizophrenia. However, further studies with larger subjects would be required to better understand the association of COMT gone polymorphism and schizophrenia.
~ T h e efficacy of risperidone in the management of attempted suicide in patients with schizophrenia Y. t)arak 1, H.Y. Knobler 2, I. Mirecki 1, D. Aizenberg 3 . 1Abarbanel MemaZ Hea#~ Center, Psyo,~ogeriatrios, Bat-Yam, Israet; 27DF, Memal HeaitJ~, iRamat-gan, Israel; 3ge;~a Meuntal Hea#J~Ceuter, Psy&ogeriatrics, Petah- Tiqoa, Israel Purpose: Mortality of schizophrenia patients, particularly from suicide is an unremitting challenge to health care professionals (Kane etal, 2003), The advent of the second generation antipsychotics (S@A) affected wmptomatology and patients quality of life. The antisuicide effects of the SGA were mostly studied with regard to clozapine. Recent publications suggest this effect may be related to other S@A as well (Barak et al, 2004). The aim of the present study was to analyze the available data on the effects of exposure to risperidone on suicidality of patients suffering from schizophrenia. Methods: Included in this analysis were studies involving open or controlled treah'nent with risperidone that involved at least 100 subjects and reported on suicide attempts. We conducted a computerized MEDLINE literature search in March 2004 using the keywords 'atypical', 'new', 'novel', 'new-generation', and 'second generation antipsychotics', the generic name risperidone and 'suicidality', 'suicide' or 'attempted suicide' Through our literature search we located and analyzed 4 studies reporting suicide attempts involving treatment with risperidone that included at least 100 subjects. In all studies we computed number of patient exposure years (PEY) reflecting the cumulative time that patients were exposed to active drug (as described by Khan etal, 2001). Results: All studies herein analyzed were published in the last 3 years. Sample size ranged from 102 to 2,607 schizophrenia patients treated by risperidone. Annual rates of attempted suicide based on patient exposure years were lower in the risperidone treated patients compared to haloperidol (1.8%, 4.1%, 5.0% and 6.4% vs 7.0%, respectively), see Table 1.
No Pts
PET-
Attempted suicide*
Altamura etal, 2003 Barak et a4 2004
103 378
i 15 145
1,8% 4,1%
Khan et al~ 2001 Conley & Mahmoud, 2001
2,607 187
858
5.0%
31
6.4%
Legend: P E Y = Pati~t ~posure years, *oomparator is haloperidol; P E ¥ %r haloperidol was 71 and suicide rate was 7,0°/0,
Conclusions: Risperidone is associated with lower rates of atterr~ted suicide amongst schizophrenia patients, The mechanism of this effect in relation to S G A pharmacology, improved compliance or others needs further elucidation,
P2. Psychotic disorders and amipsyehotics References Khan A, Khan SE, Lenthal RM, Brown WA. Symptom reduction and suicide risk among patients treated with placebo in antipsyehotio clinical trials: an analysis of the Food and Drug Administration database. Am J Psychiatry 2001; 158:1449-1454. Kane JM, Leueht S, Carpenter D, Doeherty JR Optirnizingpharmaeologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry 2003;64[suppl 12] :1-100. Barak Y, Mire&i I, Khobler H, Natan Z, Aizenberg D. Suieidality and second genexation anytipsychotics in schizophrenia patients: a casecontrolled retrospective study during a 5-year period. Psyohopharmaeology (Berl). 2004 Feb 4 [Epub].
•
Long-term weight effects of arJpJprazole and olanzapine: Results from a 26-week double-blind comparison study
W. Carson 1, R. McQuade 2, N. Abou-Gharbia 2, T. Iwamoto 3, D. Archibald 4 , E. Stock 2 . 1Otsuka America Pl~armaceuticalTne.,
Princeton, U~S,A,; 2Bristol-Myers Squibb Company, _Princeton, U~S,A,; s ©tsuka Pharmaceutical Co, Ltd, Tokyo, Japan; "~BristolMyem Squibb Company, Walling;ford, US, A, Objeetives: To compare the effects of long-term treatment with aripiprazole and olanzapine on body weight in patients with acute relapse of schizophrenia. lVIethods: A total of 317 patients were randomised to 26 weeks of treatment with aripiprazole (15-30 rag/day) or olanzapine (1020 rag/day) in this double-blind, multicentre study. The primary outcome measure was the proportion of patients experiencing significant weight gain (~>7% increase) from baseline to endpoint. Results: Significantly more olanzapine~treated patients experienced significant weight gain over the course of the study than aripiprazole-treated patients. Mean changes in body weight showed significant differences between the groups at weeks 6 and 26; at week 26 there was a mean weight gain with olanzapine treatment of 4.23 kg compared with a mean weight loss with aripiprazole treatment of 1.37 kg (p<0.001). Differences favouring aripiprazole were also seen for changes in total cholesterol, I-IDL cholesterol, and triglycerides. The rate of clinical response did not differ between aripiprazole and olanzapine, either acutely (week 6) or in the number of patients remaining in response and on therapy at week 26. Conelusiom: Aripiprazole treatment was associated with a significantly lower incidence of weight gain mid dyslipidaemias than olanzapine therapy, while clinical response was comparable between thegroups. These findings may result in a more advantageous long-term metabolic profile for patients with schizophrenia treated with afipiprazole than for those treated with olanzapine.
~ T h e short-term effect of orally disintegrating olanzapine tablets on agitalJon and cooperation in clinical practice C, van Keeringen 1, B. Gillain 2, B. van Vleymen 3, F. van den Driessche4 . 1University Hospital, Dept of Psychiatry, (~nt,
Belgium; 2UCL, Psyci#iatry, Brussels, Belgium; sEli Lilly, Benelux, Brussels, Belgium; 4St Norbertu~, Psychiatr N, Duffel, Belgium Objectives: To assess the short-term effect of the orally disintegrating olanzapine 5-40 mg on agitation, cooperation and burden to the caretaker in clinical practice.
$259
l~ethods-" 548 patients with agitation and/or non-cooperative behaviour entered an open-label observational study. Agitation and cooperation at baseline and after 24 hours were assessed with the Agitation Calmness Evaluation Scale (ACES) and a Visual Analogue Scale, respectively. Furthermore, the effect on the burden for caretakers and on the use of intra-muscular injection was assessed, Data on 480 patients were eligible for analysis. Results: Psychiatric diagnoses included schizophrenia (57.9%), bipolar mania (14.5%), and other diagnoses (27.6%). In 207/490 (42.2%) only olanzapine was added to the existing medication, while in 57.8% olanzapine was combined with other drugs. The median olanzapine dose was 20 mg (range 2.5-40 my) The ACES score improved from 2.5 (95%CI 2.4-2.6) on day 1 to 3.6 (95%C1 3.5-3.7) after 24 hours. Cooperation scores increased from 3.9 (95%C1 3.7-4.2) to 5.4 (95% CI 5.2-5.6). No baseline differences were observed between the sub-group of patients given treatment with orally disintegrating olanzapine tablets alone ('mono-therapy') or as part of a combination of drugs ('polytherapy') with respect to either diagnoses or severity of illness (mean C@I 5.1 (95% CI 4.9-5.2), including agitation (mean ACES 2.6 (95% CI 2.4-2.8). Outcome following acute treatment was also similar for the two sub-groups. Mean CGI of change score was 4.8 (95% CI 4.6-4.9), while corresponding scores in the 'poly-therapy' sub-group 4.8 (95% C1 4.6 - 4.9). Mean change in ACES scores (1.2 for both groups)showed a similar decrease in the mono-therapy and poly-therapy groups following treatment. The change in VAS scores between baseline and trea~nent was also similar for the two patient sub-groups (1.5 (95% CI 1.2-1.7) vs 1.6 (95% C1 1.3-1.9). The burden for caretakers decreased in 65% and an IM injection was avoided in 65% of the patients. Coneluslon: Adding disintegrating olanzapine tablets, alone or in combination, to the existing medication at a median dose of 20 mg markedly decreases agitation and improves cooperation within 24 hours, without excessive sedation. In addition, there is a substantial positive effect on the burden for caretakers and on the use of intra-muscular drugs.
•
Pharmacological characterisation of $R 142801 (osanetant) at clonal and native NK-3 receptors
D,R, Thomas, N, Patel, L,A, Dawson, K_gaxoEmitAKli~e,
Psychiatry CEDD, Harlot, United Kinadom SR142801 (osanetant) is a neurokinin-3 (NK-3) receptor antagonist and a potential treatment %r schizophrenia, SR142801 has been reported to be a competitive antagonist at the human cloned NK-3 receptor (Oury-Donat et al,, 1995) but an uncompetitive antagonist at the NK-3 receptor in guinea pig ileum (Beaujouan et aL, 1997), In the present study the profile of interaction of SR-142801 with the NK-3 receptor was investigated utilising [SH]-SR142801 binding and agonist-stimulated intracellular Ca2+ mobilisation, For saturation binding studies human recombinant NK-3fI-IEK293 or guinea pig cerebral cortex membranes were incubated with [3I-I]-SR142801 (Amersharn, IIK,) (0,03-6 nM) for 60 rain at 37°C in Tris I4C1 buffer (50 mlVi, pI-I 7,4) containing MgC12 (10 rnM) and BSA (0,1%), Association and dissociation rate experiments were per%rmed using 0,3 nM [3I-I]-Slk142801 and dissociation was initiatedby addition of the NK-3 receptor antagonist, SB-222200 (3 b~M) (Sarau et al., 2000) following incubation for 60 rain. H u m a n NK-3 receptor function was determined by measuring NK-B-induced Ca 2+ mobilisation in hNK-3YHEK293 cells using a fluorescence imaging plate reader
S258
habenula, or a sham procedure, were per%rmed. After a recovery period of one wee}: behavioural testing was re-initiated. The lesion caused a pronounced and long-lasting enhancement of the mean number of premature responses (significant effects of group [F(1,14)=9.9, p<0.007] and of day [F(11,154)=7.3, p<0.0001]). Additionally, by three to four weeks post-surgery, lesioned animals showed a significant decrease of choice accuracy measured by percent correct responses, t-laloperidol (0.03 mg/kg) significantly reduced the number of premature responses in lesioned and sham animals (significant effects of group [F(1,14)=8.8, p=0.01], treatment [F(2,28)=4.4, p=0.022] and no significant interaction [F(2,28)=1.1, p>0.1]). In contrast, haloperidol did not influence choice accuracy. Amphetamine increased premature responses in lesioned and sham animals without affecting choice accuracy. The effects of haloperidol and amphetamine suggest that increased premature responses may be due to acute dopaminergic hyperactivity, whereas decreased choice accuracy is a progressive deficit not attributable to such an acute effect. As increased premature responses have been attributed to either a decrease of serotonin or increase of dopamine activity, and considering that the habenula participates in the regulation of mesolimbic, mesostriatal and mesocortical monoaminergio paths (Lisoprawski etal., 1980), the results are consistent with the view that pathology of the habenula contributes to the cognitive impairments of schizophrenia by two mechanisms, first by disturbing midbrain to forebrain monoaminergic neurotransmission, and secondly by a non-dopaminergic progressive process (e.g Kelly, 1998).
References Lisoprawsld A., Herve D., Blanc G., Glowinski J. & Tassin J.R, 1980. Selective activation of the mesocortieo-frontal dopaminergie n~rons induced by lesion of the habenula in the rat. Brain Researdl. 183, 22%234. Kelly, P.H., 1998. Defective inhibition of dream-e~ents memory formation: a hypothesized mechanism in the onset and progression of symptoms of s&izcphremia. Brain Res Bull. 46, 18%97.
•
Catechol-O-methyltran sferase gene polymorphism in symptomatology of schizophrenia
C .T. Lee-.,H.K. Lee, Y.S. Kwon, K.U. Lee. :T~e Cat/~olic U-nioersity
of Korea, Departmem of Psycfgatry, Department of Psychiatry, Uijongbu city, Republic of Korea Pm'l~OSe-" Catechol-O-Methyltranferase (C©MT) gene is involved dopamine metabolism, which has been implicated to have putative role in the pathogenesis schizophrenia and aggressive behaviors. Although evidence exists for an association between aggression and schizophrenia, the pathogenesis of aggression in schizophrenia has not been established. We carried out this study to evaluate the association between schizophrenia, its psychopathologics (positive symptom, negative symptom, aggression) and COMT gone polymorphism. lVleth~l: One hundred and twenty four patients with schizophrenia by DSM-III who admitted to Uijongbu St. May's hospotal and 94 normal controls were participated in this study. The evaluation of patients was accomplished by positive & negative syndrome scale (PANSS) and overt aggression scale (OAS). The analysis of COMT gone polymosphism was perfomed using PCR method with RFLR ResuR: There was no statistically significant differences between frequencies of COMT genotype in patients and controls.
Although the average of positive & negative subscale of PANSS and OAS were not significantly different between the COMT variants, there was tendency that patients with COMT L/L have higher negative subscale of PANSS than other group. Conclusion: This result suggests that COMT gone polymorphism was not associated with development and syrrptomatology of schizophrenia. However, further studies with larger subjects would be required to better understand the association of COMT gone polymorphism and schizophrenia.
~ T h e efficacy of risperidone in the management of attempted suicide in patients with schizophrenia Y. t)arak 1, H.Y. Knobler 2, I. Mirecki 1, D. Aizenberg 3 . 1Abarbanel MemaZ Hea#~ Center, Psyo,~ogeriatrios, Bat-Yam, Israet; 27DF, Memal HeaitJ~, iRamat-gan, Israel; 3ge;~a Meuntal Hea#J~Ceuter, Psy&ogeriatrics, Petah- Tiqoa, Israel Purpose: Mortality of schizophrenia patients, particularly from suicide is an unremitting challenge to health care professionals (Kane etal, 2003), The advent of the second generation antipsychotics (S@A) affected wmptomatology and patients quality of life. The antisuicide effects of the SGA were mostly studied with regard to clozapine. Recent publications suggest this effect may be related to other S@A as well (Barak et al, 2004). The aim of the present study was to analyze the available data on the effects of exposure to risperidone on suicidality of patients suffering from schizophrenia. Methods: Included in this analysis were studies involving open or controlled treah'nent with risperidone that involved at least 100 subjects and reported on suicide attempts. We conducted a computerized MEDLINE literature search in March 2004 using the keywords 'atypical', 'new', 'novel', 'new-generation', and 'second generation antipsychotics', the generic name risperidone and 'suicidality', 'suicide' or 'attempted suicide' Through our literature search we located and analyzed 4 studies reporting suicide attempts involving treatment with risperidone that included at least 100 subjects. In all studies we computed number of patient exposure years (PEY) reflecting the cumulative time that patients were exposed to active drug (as described by Khan etal, 2001). Results: All studies herein analyzed were published in the last 3 years. Sample size ranged from 102 to 2,607 schizophrenia patients treated by risperidone. Annual rates of attempted suicide based on patient exposure years were lower in the risperidone treated patients compared to haloperidol (1.8%, 4.1%, 5.0% and 6.4% vs 7.0%, respectively), see Table 1.
No Pts
PET-
Attempted suicide*
Altamura etal, 2003 Barak et a4 2004
103 378
i 15 145
1,8% 4,1%
Khan et al~ 2001 Conley & Mahmoud, 2001
2,607 187
858
5.0%
31
6.4%
Legend: P E Y = Pati~t ~posure years, *oomparator is haloperidol; P E ¥ %r haloperidol was 71 and suicide rate was 7,0°/0,
Conclusions: Risperidone is associated with lower rates of atterr~ted suicide amongst schizophrenia patients, The mechanism of this effect in relation to S G A pharmacology, improved compliance or others needs further elucidation,
P2. Psychotic disorders and amipsyehotics References Khan A, Khan SE, Lenthal RM, Brown WA. Symptom reduction and suicide risk among patients treated with placebo in antipsyehotio clinical trials: an analysis of the Food and Drug Administration database. Am J Psychiatry 2001; 158:1449-1454. Kane JM, Leueht S, Carpenter D, Doeherty JR Optirnizingpharmaeologic treatment of psychotic disorders. Introduction: methods, commentary, and summary. J Clin Psychiatry 2003;64[suppl 12] :1-100. Barak Y, Mire&i I, Khobler H, Natan Z, Aizenberg D. Suieidality and second genexation anytipsychotics in schizophrenia patients: a casecontrolled retrospective study during a 5-year period. Psyohopharmaeology (Berl). 2004 Feb 4 [Epub].
•
Long-term weight effects of arJpJprazole and olanzapine: Results from a 26-week double-blind comparison study
W. Carson 1, R. McQuade 2, N. Abou-Gharbia 2, T. Iwamoto 3, D. Archibald 4 , E. Stock 2 . 1Otsuka America Pl~armaceuticalTne.,
Princeton, U~S,A,; 2Bristol-Myers Squibb Company, _Princeton, U~S,A,; s ©tsuka Pharmaceutical Co, Ltd, Tokyo, Japan; "~BristolMyem Squibb Company, Walling;ford, US, A, Objeetives: To compare the effects of long-term treatment with aripiprazole and olanzapine on body weight in patients with acute relapse of schizophrenia. lVIethods: A total of 317 patients were randomised to 26 weeks of treatment with aripiprazole (15-30 rag/day) or olanzapine (1020 rag/day) in this double-blind, multicentre study. The primary outcome measure was the proportion of patients experiencing significant weight gain (~>7% increase) from baseline to endpoint. Results: Significantly more olanzapine~treated patients experienced significant weight gain over the course of the study than aripiprazole-treated patients. Mean changes in body weight showed significant differences between the groups at weeks 6 and 26; at week 26 there was a mean weight gain with olanzapine treatment of 4.23 kg compared with a mean weight loss with aripiprazole treatment of 1.37 kg (p<0.001). Differences favouring aripiprazole were also seen for changes in total cholesterol, I-IDL cholesterol, and triglycerides. The rate of clinical response did not differ between aripiprazole and olanzapine, either acutely (week 6) or in the number of patients remaining in response and on therapy at week 26. Conelusiom: Aripiprazole treatment was associated with a significantly lower incidence of weight gain mid dyslipidaemias than olanzapine therapy, while clinical response was comparable between thegroups. These findings may result in a more advantageous long-term metabolic profile for patients with schizophrenia treated with afipiprazole than for those treated with olanzapine.
~ T h e short-term effect of orally disintegrating olanzapine tablets on agitalJon and cooperation in clinical practice C, van Keeringen 1, B. Gillain 2, B. van Vleymen 3, F. van den Driessche4 . 1University Hospital, Dept of Psychiatry, (~nt,
Belgium; 2UCL, Psyci#iatry, Brussels, Belgium; sEli Lilly, Benelux, Brussels, Belgium; 4St Norbertu~, Psychiatr N, Duffel, Belgium Objectives: To assess the short-term effect of the orally disintegrating olanzapine 5-40 mg on agitation, cooperation and burden to the caretaker in clinical practice.
$259
l~ethods-" 548 patients with agitation and/or non-cooperative behaviour entered an open-label observational study. Agitation and cooperation at baseline and after 24 hours were assessed with the Agitation Calmness Evaluation Scale (ACES) and a Visual Analogue Scale, respectively. Furthermore, the effect on the burden for caretakers and on the use of intra-muscular injection was assessed, Data on 480 patients were eligible for analysis. Results: Psychiatric diagnoses included schizophrenia (57.9%), bipolar mania (14.5%), and other diagnoses (27.6%). In 207/490 (42.2%) only olanzapine was added to the existing medication, while in 57.8% olanzapine was combined with other drugs. The median olanzapine dose was 20 mg (range 2.5-40 my) The ACES score improved from 2.5 (95%CI 2.4-2.6) on day 1 to 3.6 (95%C1 3.5-3.7) after 24 hours. Cooperation scores increased from 3.9 (95%C1 3.7-4.2) to 5.4 (95% CI 5.2-5.6). No baseline differences were observed between the sub-group of patients given treatment with orally disintegrating olanzapine tablets alone ('mono-therapy') or as part of a combination of drugs ('polytherapy') with respect to either diagnoses or severity of illness (mean C@I 5.1 (95% CI 4.9-5.2), including agitation (mean ACES 2.6 (95% CI 2.4-2.8). Outcome following acute treatment was also similar for the two sub-groups. Mean CGI of change score was 4.8 (95% CI 4.6-4.9), while corresponding scores in the 'poly-therapy' sub-group 4.8 (95% C1 4.6 - 4.9). Mean change in ACES scores (1.2 for both groups)showed a similar decrease in the mono-therapy and poly-therapy groups following treatment. The change in VAS scores between baseline and trea~nent was also similar for the two patient sub-groups (1.5 (95% CI 1.2-1.7) vs 1.6 (95% C1 1.3-1.9). The burden for caretakers decreased in 65% and an IM injection was avoided in 65% of the patients. Coneluslon: Adding disintegrating olanzapine tablets, alone or in combination, to the existing medication at a median dose of 20 mg markedly decreases agitation and improves cooperation within 24 hours, without excessive sedation. In addition, there is a substantial positive effect on the burden for caretakers and on the use of intra-muscular drugs.
•
Pharmacological characterisation of $R 142801 (osanetant) at clonal and native NK-3 receptors
D,R, Thomas, N, Patel, L,A, Dawson, K_gaxoEmitAKli~e,
Psychiatry CEDD, Harlot, United Kinadom SR142801 (osanetant) is a neurokinin-3 (NK-3) receptor antagonist and a potential treatment %r schizophrenia, SR142801 has been reported to be a competitive antagonist at the human cloned NK-3 receptor (Oury-Donat et al,, 1995) but an uncompetitive antagonist at the NK-3 receptor in guinea pig ileum (Beaujouan et aL, 1997), In the present study the profile of interaction of SR-142801 with the NK-3 receptor was investigated utilising [SH]-SR142801 binding and agonist-stimulated intracellular Ca2+ mobilisation, For saturation binding studies human recombinant NK-3fI-IEK293 or guinea pig cerebral cortex membranes were incubated with [3I-I]-SR142801 (Amersharn, IIK,) (0,03-6 nM) for 60 rain at 37°C in Tris I4C1 buffer (50 mlVi, pI-I 7,4) containing MgC12 (10 rnM) and BSA (0,1%), Association and dissociation rate experiments were per%rmed using 0,3 nM [3I-I]-Slk142801 and dissociation was initiatedby addition of the NK-3 receptor antagonist, SB-222200 (3 b~M) (Sarau et al., 2000) following incubation for 60 rain. H u m a n NK-3 receptor function was determined by measuring NK-B-induced Ca 2+ mobilisation in hNK-3YHEK293 cells using a fluorescence imaging plate reader