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Ginkgo biloba extract (EGb 761) modifies catalepsy induced by haloperidol or nitric oxide synthase inhibitor in mice
P2. Psychotic disorders and antipsychotics p=0.03). The incidence of treatment emergent adverse events (TEAE) occurring with iY10% frequency was similar for the two groups, apart from QT prolongation and abnormal ejaculation for sertindole, and insomnia, asthenia, and EPS for risperidone. The proportion of patients who reported EPS-related TEAEs in the risperidone-treated group was greater than that of sertindoletreated patients (risperidone: 28%; sertindole: 19%), though this difference was not statistically significant. Scores in movement rating scales (Simpson-Angus Scale (SAS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS)) improved for both treatment groups. Sertindole-treated patients tended to improve slightly more than risperidone-treated patients on the SAS and BAS scales, although there were no statistically significant differences between treatments. This may be due to the reduced power caused by premature termination of the study. Conclusion: The study showed sertindole to be superior to risperidone with respect to efficacy and equally well tolerated.
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Prolactin serum levels after long term risperidone treatment
$301
within 12 months returned to within normal limits (mean 16.1 ng/ml, SD=13.2). 89% of children had prolactin levels below 30 ng/mL at the 12 month point and only 6 % had prolactin related side effects at any time during the year. No correlation between risperidone dose, prolactin levels and prolactin-related side effects was found, and decrease in prolactin levels over the 48 weeks occurred in patients compliant with medication. Conclusion: A rise in mean serum prolactin (PRL) level in risperidone-treated children between 4-7 weeks. More significantly, PRL declined from week 8 onward of treatment to within normal limits between weeks 40-54. Risperidone is generally not associated with persistent and raised serum prolactin levels in continuation and maintenance treatment in the majority of children. No correlation was found between serum prolactin levels and prolactin related side effects.
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Ginkgo biloba extract (EGb 761) modifies catalepsy induced by haloperidol or nitric oxide synthase inhibitor in mice
R.M.W. De Oliveira 1, L. Fontana 1, E.A. Del Bel 2. 1State G. De Smedt 1 , C, Binder2, R. Findling 3, V. Kusumakar 4.
l Johnson & Johnson PRD, Beerse, Belgium; 2janssen Ortho Inc., Clinical, Toronto, Canada," 3 University Hospitals of Cleveland, Child and Adolescent Psychiatry, Cleveland, U.S.A.; 4Dalhousie University, Psychiatry, Halifax, Canada Purpose of the study: From a cumulative database of children treated with risperidone for up to 52 weeks in five studies we analyzed the: 1. Trend of serum prolactin (PRL) levels at multiple time points 2. Relationship, if any, between serum prolactin (PRL) levels and prolactin-related side-effects Methods: Five study databases of risperidone treated children (n=709) were merged. The children were 5-15 years with a subaverage IQ (IQ 36-85),with a variety of disruptive behaviour disorders (DBD) as per the Diagnostic and Statistical Manual Fourth Version (DSM IV). Doses of risperidone in all trials ranged from 0.02 mg/kg to 0.06 mg/kg per day. Patients were exposed to risperidone for up to 48 weeks. Prolactin data were collected at baseline and endpoint during the double-blind trials and at weeks 4, 12, 24, 36, and 48. Serum prolactin samples were obtained in the morning prior to first dose of study medication. Adverse events were captured by spontaneous report of the parent/child at each clinic visit. Patients' vital signs, weight, and Tanner stage were obtained during the trials. Summary of results and statistical assessments: The data eligible for the primary analysis population (PAP) (n=592) consisted of children with a pre-dose and at least one post-dose prolactin observation at/or after week 4. Correlational analyses were performed on prolactin related side effects, dose, and medication compliance. Similarities and differences between PAP and non-PAP populations will be presented. The average age of the children was 9.9 (SD=2.5). 82.6% were boys and 17.4% girls. 73% were in Tanner Stage 1, 14.4% in Tanner Stage 2 and the remainder were in Tanner Stage 3-5. 39.9% of the children had borderline mental Retardation, 42% mild mental retardation and the rest had moderate mental retardation. Mean serum prolactin levels at baseline (pre-dose) were 7.8 (SD=7.2; range: 2.0-76.5) ng/ml, and rose during acute treatment with risperidone to 29.4 (SD=16.5) ng/ml during weeks 4-7. However, thereafter, in the continuation and maintenance phase of treatment with risperidone, from as early as 8 weeks, mean levels of PRL decreased and
University of Maring6, Department of Pharmacy and Pharmacology, Maring6, Brazil; 2School of Odontology, University of Sao Paulo, Department of Physiology, Ribeirao Preto, Brazil The Ginkgo biloba extract, designated EGb 761 (Tebonin, Byk Quimica), is a standardized mixture of active substances, including flavonoid glycosides and terpenoids obtained from green leaves of the Ginkgo biloba tree. Clinical trials support the potential therapeutic usefulness of EGb 761 in the treatment of cerebral insufficiency, mild cognitive impairments and claudication. However, the mechanisms underlying these effects are not yet well established. Numerous studies have shown that EGb 761 is capable of scavenging free radicals such as nitric oxide (NO) and reducing calcium-stimulated intracellular events (Bastianetto et al., 2000). In mice, systemic administration of N-nitro-Larginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in a dose-dependent manner. Del Bel et al (1998) have demonstrated that L-NOARG has an additive effect with haloperidol, possibly by interfering with the striatal dopaminergic system. Objective: the present work aimed to investigate if the EGb 761 was able to modify the catalepsy induced by L-NOARG or haloperidol in mice. Methods: catalepsy was evaluated according to the standard bar-hanging procedure by placing the animals with both forelegs over a horizontal glass bar (0.5 cm o.d.) for 5 minutes. Experiment 1: animals (10--12/group) received a single EGb 761 (100 mg/Kg) or water oral administration, followed, 30 minutes later, by a second haloperidol (2mg/kg; Haldol, Janssen), L-NOARG (40 mg/Kg; Sigma) or saline i.p. injection. The catalepsy test was performed 10, 60 and 120 minutes after the last administration. Experiment 2: subchronic treatment was realised submitting the animals (10-12/group) to the same protocol described in experiment 1, including the catalepsy evaluation, followed by, twice a day for 4 days, an oral administration of either water or EGb 761. In the fifth day the animals received again a single haloperidol, L-NOARG or saline i.p. injections and were submitted to the behavioural test. Results: Acute treatment with EGb 761 did not modify the catalepsy induced by L-NOARG or haloperidol. However, subchronic treatment with EGb 761 induced a significant increase
P2. Psychotic disorders and antipsychotics
$302
in the cataleptogenic effects produced by both L-NOARG and haloperidol (treatment x day x time, F4,60=8,24, p<0.001, Duncan test). Conclusions: The results showed that subchronic administration of EGb 761 interferes with drugs affecting the control of motor behaviour in mice. This effect may take part in potential interaction between clinically utilised drugs.
References [1] Del Bel, E.A.; Silva, C.A.; Guimaraes, F.S. 1998. Catalepsy induced by nitric oxide inhibitors. Gen. Pharmacol. 30, 245-248. [2] Bastianetto,.S.; Zheng, W.; Quirion, R. 2000. The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxideinduced toxicity: involvement of its flavonoids constituents and protein kinase C. J. Neuroch.74, 22682277.
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Efficacy of amisulpride vs risperidone in the long-term treatment of chronic schizophrenia: Results from a 12 month double-blind study
W. Rein, O. Fleurot. Sanofi-Synthelabo, Chilly-Mazarin, France Aims: To compare the long-term efficacy and functional effects of amisulpride with those of risperidone in patients with chronic schizophrenia. Methods: In- or out-patients of either sex (aged 18-65 years) with chronic schizophrenia (disease duration at least 2 years) of the paranoid, disorganised, undifferentiated or residual type (DSM-IV) and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 were included in this double-blind, multicentre study. Following a 2-6 day placebo washout, patients were randomised to amisulpride (400-1000 mg/day) or risperidone (4-10 mg/day) for 6 months. All patients who remained in the study after 6 months were entered into a further 6-month doubleblind extension phase during which they continued on amisulpride (200-800 rag/day) or risperidone (2-8 mg/day). Efficacy assessments included the PANSS total, negative, positive and global psychopathology scores, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Bech Rafaelsen Melancholia Scale (BRMS), the Clinical Global Impression (CGI) severity of illness and global improvement scales and the Social and Occupational Functioning Assessment Scale (SOFAS). Efficacy analyses were performed on a maintenance population (patients exposed to treatment for >8 weeks, with at least one evaluation after that visit). The primary objective of the study was to demonstrate non inferiority of amisulpride compared to risperidone, using PANSS total score change from baseline with a non inferiority limit of 8 points defined in the protocol. All other efficacy parameters were analysed using a superiority hypothesis. Results: 310 Patients were randomised to treatment. The proportion of patients completing the study was significantly higher in the amisulpride than in the risperidone group (48% vs. 36%, p=0.033). Premature discontinuation also occurred significantly earlier with risperidone than with amisulpride (p=0.0478). The maintenance population consisted of 244 patients (121 amisulpride and 123 risperidone). Amisulpride and risperidone were both markedly effective, with mean reductions in PANSS total score of 30.4 and 30.3, respectively, after 12 months (95% two sided confidence interval [-6.2;6.1]). This was confirmed by the BPRS total score, PANSS positive and psychopathology subscales, CGI severity of illness scale and BRMS. The PANSS negative subscale, the SANS and the CGI global improvement scale showed a trend
towards greater improvement with amisulpride. Amisulpride also showed advantages with regard to maintenance of effect. A PANS S improvement of >20% at 2 months was achieved by 92% and 89% of amisulpride and risperidone treated patients, respectively; this effect was maintained until 12 months in 60% of amisulpridetreated and 47% of risperidone-treated patients (p=0.05). Both groups experienced a marked improvement in their social and occupational functioning abilities as determined by the SOFAS. Conclusions: Long-term treatment with amisulpride was at least as effective as risperidone in patients with chronic schizophrenia, and there was a tendency for amisulpride to have superior effects with regard to negative symptoms and maintenance of effect.
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Identification of peripheral genetic markers of schizophrenia with cDNA chips
G. Szekeres 1, A. Zvara 2, L. Hackler Jr. 2, Z. Janka 1, M. Sfintha a, L. Puskfis 2. l University of Szeged, Department of Psychiatry,
Szeged, Hungary; 2Biological Research Centre, DNA-chip Laboratory, Szeged, Hungary; 3Biological Research Centre, Biochemical Institute, Szeged, Hungary Purpose: At present the diagnosis of schizophrenia rests on clinical signs and symptoms alone. The aim of our investigations is to find peripheral genetic markers characteristic of schizophrenia in order help early and exact diagnosis. Methods: Several elements of dopamine, serotonin and glutamate neurotransmitter systems such as genes encoding their receptors as well as proteins necessary to synthetize and metabolize these compounds are expressed in lymphocytes. On the grounds of this opportunity we examined gene expression patterns of individual peripheral blood lymphocytes of different patient groups compared to matched healthy control group using cDNA chip and RealTime polymerase chain reaction (PCR) techniques. Patients were divided to responder/non-responder, drugfree/treated, clinically stable/acutely psychotic, deficit/non-deficit groups and matched according to age and sex. From lymphocytes we extracted total RNA, then made pools. In each pool we sorted 8-10 appropriate samples. Total RNAs were amplificated in two steps and then were labeled with Cy3 and Cy5. Labeled samples were hybridized on cDNA chips. Each cDNA chip contained 3200 human genes in duplicates, the majority of clones were from human T-lymphocyte cDNA libraries. Results: We identified several genes with different expression in patient and control groups. Some of the obtained differences were confirmed by RealTime polymerase chain reaction corroborating the data resulting from DNA chip analyses. ConcLusions: We found differences between gene expressions of certain patient groups and controls. This approach can serve as a possible genetic way for detecting schizophrenia earlier and independent of full-blown manifest clinical symptoms. Further control experiments are required to develop a reliable method to diagnose schizophrenia at an early stage.
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Prolactin serum levels after long term risperidone treatment
$301
within 12 months returned to within normal limits (mean 16.1 ng/ml, SD=13.2). 89% of children had prolactin levels below 30 ng/mL at the 12 month point and only 6 % had prolactin related side effects at any time during the year. No correlation between risperidone dose, prolactin levels and prolactin-related side effects was found, and decrease in prolactin levels over the 48 weeks occurred in patients compliant with medication. Conclusion: A rise in mean serum prolactin (PRL) level in risperidone-treated children between 4-7 weeks. More significantly, PRL declined from week 8 onward of treatment to within normal limits between weeks 40-54. Risperidone is generally not associated with persistent and raised serum prolactin levels in continuation and maintenance treatment in the majority of children. No correlation was found between serum prolactin levels and prolactin related side effects.
•
Ginkgo biloba extract (EGb 761) modifies catalepsy induced by haloperidol or nitric oxide synthase inhibitor in mice
R.M.W. De Oliveira 1, L. Fontana 1, E.A. Del Bel 2. 1State G. De Smedt 1 , C, Binder2, R. Findling 3, V. Kusumakar 4.
l Johnson & Johnson PRD, Beerse, Belgium; 2janssen Ortho Inc., Clinical, Toronto, Canada," 3 University Hospitals of Cleveland, Child and Adolescent Psychiatry, Cleveland, U.S.A.; 4Dalhousie University, Psychiatry, Halifax, Canada Purpose of the study: From a cumulative database of children treated with risperidone for up to 52 weeks in five studies we analyzed the: 1. Trend of serum prolactin (PRL) levels at multiple time points 2. Relationship, if any, between serum prolactin (PRL) levels and prolactin-related side-effects Methods: Five study databases of risperidone treated children (n=709) were merged. The children were 5-15 years with a subaverage IQ (IQ 36-85),with a variety of disruptive behaviour disorders (DBD) as per the Diagnostic and Statistical Manual Fourth Version (DSM IV). Doses of risperidone in all trials ranged from 0.02 mg/kg to 0.06 mg/kg per day. Patients were exposed to risperidone for up to 48 weeks. Prolactin data were collected at baseline and endpoint during the double-blind trials and at weeks 4, 12, 24, 36, and 48. Serum prolactin samples were obtained in the morning prior to first dose of study medication. Adverse events were captured by spontaneous report of the parent/child at each clinic visit. Patients' vital signs, weight, and Tanner stage were obtained during the trials. Summary of results and statistical assessments: The data eligible for the primary analysis population (PAP) (n=592) consisted of children with a pre-dose and at least one post-dose prolactin observation at/or after week 4. Correlational analyses were performed on prolactin related side effects, dose, and medication compliance. Similarities and differences between PAP and non-PAP populations will be presented. The average age of the children was 9.9 (SD=2.5). 82.6% were boys and 17.4% girls. 73% were in Tanner Stage 1, 14.4% in Tanner Stage 2 and the remainder were in Tanner Stage 3-5. 39.9% of the children had borderline mental Retardation, 42% mild mental retardation and the rest had moderate mental retardation. Mean serum prolactin levels at baseline (pre-dose) were 7.8 (SD=7.2; range: 2.0-76.5) ng/ml, and rose during acute treatment with risperidone to 29.4 (SD=16.5) ng/ml during weeks 4-7. However, thereafter, in the continuation and maintenance phase of treatment with risperidone, from as early as 8 weeks, mean levels of PRL decreased and
University of Maring6, Department of Pharmacy and Pharmacology, Maring6, Brazil; 2School of Odontology, University of Sao Paulo, Department of Physiology, Ribeirao Preto, Brazil The Ginkgo biloba extract, designated EGb 761 (Tebonin, Byk Quimica), is a standardized mixture of active substances, including flavonoid glycosides and terpenoids obtained from green leaves of the Ginkgo biloba tree. Clinical trials support the potential therapeutic usefulness of EGb 761 in the treatment of cerebral insufficiency, mild cognitive impairments and claudication. However, the mechanisms underlying these effects are not yet well established. Numerous studies have shown that EGb 761 is capable of scavenging free radicals such as nitric oxide (NO) and reducing calcium-stimulated intracellular events (Bastianetto et al., 2000). In mice, systemic administration of N-nitro-Larginine (L-NOARG), an inhibitor of nitric oxide synthase, induces catalepsy in a dose-dependent manner. Del Bel et al (1998) have demonstrated that L-NOARG has an additive effect with haloperidol, possibly by interfering with the striatal dopaminergic system. Objective: the present work aimed to investigate if the EGb 761 was able to modify the catalepsy induced by L-NOARG or haloperidol in mice. Methods: catalepsy was evaluated according to the standard bar-hanging procedure by placing the animals with both forelegs over a horizontal glass bar (0.5 cm o.d.) for 5 minutes. Experiment 1: animals (10--12/group) received a single EGb 761 (100 mg/Kg) or water oral administration, followed, 30 minutes later, by a second haloperidol (2mg/kg; Haldol, Janssen), L-NOARG (40 mg/Kg; Sigma) or saline i.p. injection. The catalepsy test was performed 10, 60 and 120 minutes after the last administration. Experiment 2: subchronic treatment was realised submitting the animals (10-12/group) to the same protocol described in experiment 1, including the catalepsy evaluation, followed by, twice a day for 4 days, an oral administration of either water or EGb 761. In the fifth day the animals received again a single haloperidol, L-NOARG or saline i.p. injections and were submitted to the behavioural test. Results: Acute treatment with EGb 761 did not modify the catalepsy induced by L-NOARG or haloperidol. However, subchronic treatment with EGb 761 induced a significant increase
P2. Psychotic disorders and antipsychotics
$302
in the cataleptogenic effects produced by both L-NOARG and haloperidol (treatment x day x time, F4,60=8,24, p<0.001, Duncan test). Conclusions: The results showed that subchronic administration of EGb 761 interferes with drugs affecting the control of motor behaviour in mice. This effect may take part in potential interaction between clinically utilised drugs.
References [1] Del Bel, E.A.; Silva, C.A.; Guimaraes, F.S. 1998. Catalepsy induced by nitric oxide inhibitors. Gen. Pharmacol. 30, 245-248. [2] Bastianetto,.S.; Zheng, W.; Quirion, R. 2000. The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxideinduced toxicity: involvement of its flavonoids constituents and protein kinase C. J. Neuroch.74, 22682277.
•
Efficacy of amisulpride vs risperidone in the long-term treatment of chronic schizophrenia: Results from a 12 month double-blind study
W. Rein, O. Fleurot. Sanofi-Synthelabo, Chilly-Mazarin, France Aims: To compare the long-term efficacy and functional effects of amisulpride with those of risperidone in patients with chronic schizophrenia. Methods: In- or out-patients of either sex (aged 18-65 years) with chronic schizophrenia (disease duration at least 2 years) of the paranoid, disorganised, undifferentiated or residual type (DSM-IV) and a Positive and Negative Syndrome Scale (PANSS) total score of 60-120 were included in this double-blind, multicentre study. Following a 2-6 day placebo washout, patients were randomised to amisulpride (400-1000 mg/day) or risperidone (4-10 mg/day) for 6 months. All patients who remained in the study after 6 months were entered into a further 6-month doubleblind extension phase during which they continued on amisulpride (200-800 rag/day) or risperidone (2-8 mg/day). Efficacy assessments included the PANSS total, negative, positive and global psychopathology scores, the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Bech Rafaelsen Melancholia Scale (BRMS), the Clinical Global Impression (CGI) severity of illness and global improvement scales and the Social and Occupational Functioning Assessment Scale (SOFAS). Efficacy analyses were performed on a maintenance population (patients exposed to treatment for >8 weeks, with at least one evaluation after that visit). The primary objective of the study was to demonstrate non inferiority of amisulpride compared to risperidone, using PANSS total score change from baseline with a non inferiority limit of 8 points defined in the protocol. All other efficacy parameters were analysed using a superiority hypothesis. Results: 310 Patients were randomised to treatment. The proportion of patients completing the study was significantly higher in the amisulpride than in the risperidone group (48% vs. 36%, p=0.033). Premature discontinuation also occurred significantly earlier with risperidone than with amisulpride (p=0.0478). The maintenance population consisted of 244 patients (121 amisulpride and 123 risperidone). Amisulpride and risperidone were both markedly effective, with mean reductions in PANSS total score of 30.4 and 30.3, respectively, after 12 months (95% two sided confidence interval [-6.2;6.1]). This was confirmed by the BPRS total score, PANSS positive and psychopathology subscales, CGI severity of illness scale and BRMS. The PANSS negative subscale, the SANS and the CGI global improvement scale showed a trend
towards greater improvement with amisulpride. Amisulpride also showed advantages with regard to maintenance of effect. A PANS S improvement of >20% at 2 months was achieved by 92% and 89% of amisulpride and risperidone treated patients, respectively; this effect was maintained until 12 months in 60% of amisulpridetreated and 47% of risperidone-treated patients (p=0.05). Both groups experienced a marked improvement in their social and occupational functioning abilities as determined by the SOFAS. Conclusions: Long-term treatment with amisulpride was at least as effective as risperidone in patients with chronic schizophrenia, and there was a tendency for amisulpride to have superior effects with regard to negative symptoms and maintenance of effect.
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Identification of peripheral genetic markers of schizophrenia with cDNA chips
G. Szekeres 1, A. Zvara 2, L. Hackler Jr. 2, Z. Janka 1, M. Sfintha a, L. Puskfis 2. l University of Szeged, Department of Psychiatry,
Szeged, Hungary; 2Biological Research Centre, DNA-chip Laboratory, Szeged, Hungary; 3Biological Research Centre, Biochemical Institute, Szeged, Hungary Purpose: At present the diagnosis of schizophrenia rests on clinical signs and symptoms alone. The aim of our investigations is to find peripheral genetic markers characteristic of schizophrenia in order help early and exact diagnosis. Methods: Several elements of dopamine, serotonin and glutamate neurotransmitter systems such as genes encoding their receptors as well as proteins necessary to synthetize and metabolize these compounds are expressed in lymphocytes. On the grounds of this opportunity we examined gene expression patterns of individual peripheral blood lymphocytes of different patient groups compared to matched healthy control group using cDNA chip and RealTime polymerase chain reaction (PCR) techniques. Patients were divided to responder/non-responder, drugfree/treated, clinically stable/acutely psychotic, deficit/non-deficit groups and matched according to age and sex. From lymphocytes we extracted total RNA, then made pools. In each pool we sorted 8-10 appropriate samples. Total RNAs were amplificated in two steps and then were labeled with Cy3 and Cy5. Labeled samples were hybridized on cDNA chips. Each cDNA chip contained 3200 human genes in duplicates, the majority of clones were from human T-lymphocyte cDNA libraries. Results: We identified several genes with different expression in patient and control groups. Some of the obtained differences were confirmed by RealTime polymerase chain reaction corroborating the data resulting from DNA chip analyses. ConcLusions: We found differences between gene expressions of certain patient groups and controls. This approach can serve as a possible genetic way for detecting schizophrenia earlier and independent of full-blown manifest clinical symptoms. Further control experiments are required to develop a reliable method to diagnose schizophrenia at an early stage.