- Email: [email protected]
P.3.17 The effects of modafinil on cognitive and emotional functions in the first episode of psychosis
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Clinical neuropsychopharmacology
favour to patients receiving oxcarbazepine treatment (0.33±6.02 and 4.00±7.30 respectively, p = 0.0688). No differences were found between the groups in the BISCognitive (p = 0.4494) and BIS-Impulsiveness subscales (p = 0.1786). Scores for secondary efficacy such as CGI and HAMA did not show difference between both groups at endpoint. Although without statistically significant difference between the groups, higher GAF score was observed in the oxcarbazepine group at final visit (2.37±12.57 and −1.48±15.31; p = 0.077). Conclusion: To our knowledge, this is the first placebo-controlled, randomized clinical trials showing the superiority of adjunctive treatment of oxcarbazepine over placebo in the long-term treatment of impulsivity. Our results suggest that oxcarbazepine may play a role in the treatment and prevention of impulsive-control disorders in bipolar patients. Furthermore, there was a trend for patients receiving co-therapy oxcarbazepine plus lithium towards a better functioning than patients on lithium monotherapy. Reference(s) [1] Swann, A.C., Pazzaglia, P., Nicholls, A., Dougherty, D.M., Moeller, F.G., 2003, Impulsivity and phase of illness in bipolar disorder. J Affect Disord Jan; 73(1−2): 105–111. [2] Popova, E., Leighton, C., Bernabarre, A., Bernardo, M., Vieta, E., 2007, Oxcarbazepine in the treatment of bipolar and schizoaffective disorders. Expert Rev Neurother Jun; 7(6): 617–626. [3] Vieta, E., Cruz, N., Garc´ıa-Campayo, J., de Arce, R., Manuel Crespo, J., Vall`es, V., P´erez-Blanco, J., Roca, E., Manuel Olivares, J., Mor´ın˜ igo, A., Fern´andez-Villamor, R., Comes, M., 2008, A doubleblind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol Jun; 11(4): 445–452. P.3.17 The effects of modafinil on cognitive and emotional functions in the first episode of psychosis L. Scoriels1 ° , J. Barnett1 , G. Murray1 , B. Sahakian1 , S. Cherukuru2 , M. Fielding2 , F. Cheng2 , P. Jones1 . 1 University of Cambridge, Psychiatry, Cambridge, United Kingdom; 2 Cambridgeshire and Peterborough Mental Heath NHS Trust, Cameo, Cambridge, United Kingdom Cognitive and emotional impairments are important determinants of functional outcome in schizophrenia. People suffering from first-episode psychosis (FEP) also
show these dysfunctions and current antipsychotic drugs do not help. Modafinil is a central nervous system wake-promoting agent indicated for the treatment of narcolepsy [1]. Previous studies have shown that modafinil can enhance mood, attention, memory and executive functions in healthy volunteers [2], schizophrenia [3] and bipolar depression. Following the research into the effects of modafinil in chronic schizophrenia, we aimed to establish the role of modafinil in the adjuvant treatment of schizophrenia in the first episode of psychotic illness, a time when strict diagnosis is often difficult to establish but when therapeutic endeavor is arguably most vital. A within-subject, randomised, double-blind, placebocontrolled crossover study is being carried out. To date, 27 patients attended on two occasions separated by at least one week. On each occasion, patients received either a single dose of 200 mg modafinil or a placebo prior to cognitive assessment. Analysis of variance (ANOVA) for repeated measures was carried out on our preliminary data and a post-hoc analysis was run for subgroups of high and low performance levels (as determined by premorbidIQ at baseline) on the basis the performance of patients with schizophrenia has known heterogeneity, drug effects may relay to their baseline levels of performance and our ANOVA revealed many significant effects of performance levels on the outcome measures.Our preliminary results on ANOVA revealed a significant improvement on the digit backward task (F(22,1) = 6.862, p = 0.016) * a measure of working memory – and a trend for improvement on the digit forward task (F(22,1) = 4.05, p = 0.057) with modafinil. Post-hoc analysis revealed that only high performers improved significantly on digit backward (F(12,1) = 7.837, p = 0.016) and had a trend for improvement on digit forward (F(12,1) = 3.782, p = 0.076) with the drug. Moreover, ANOVA measures also revealed a trend for improvement in face recognition (F(22,1) = 3.239, p = 0.086) and emotional face recognition (F(22,1) = 4.179, p = 0.053) with modafinil. Sad faces recognition were significantly improved (F(22,1) = 8.526, p = 0.008) with the drug. Post-hoc analysis showed significant improvement in face recognition for low performers (F(12,1) = 6.598, p = 0.028), but not for high performers. Whereas modafinil revealed a significant improvement in emotional face recognition (F(12,1) = 5.205, p = 0.042) for high performers, but not for low performers. Sad faces were recognized significantly better (F(12,1) = 6.885, p = 0.022) only by high performers.Modafinil improves working memory in the first episode of psychosis. This confirms the previous results found in chronic schizophrenia, with the additional information that only high performers seem to benefit from the drug. However, a new and more interesting result, is that modafinil also seems to improve face recognition in first episode psychosis patients. Low
Clinical neuropsychopharmacology performers improved their ability to recognize faces with the drug, but this improvement did not seem to be sufficient to process more complicated information, such as the discrimination of emotional faces, for which only high performers, who did not have problems in recognizing faces, improved with modafinil administration. Reference(s) [1] Minzenberg, M.J., Carter, C.S., 2008, Modafinil: A review of neurochemical actions and effects on cognition 33, 1477–1502. [2] Muller, U., Steffenhagen, N., Regenthal, R., Bublak, P., 2004, Effects of modafinil on working memory processes in humans 177: 161–169. [3] Turner, D.C., Clark, L., Pomarol-Clotet, E., McKenna, P., Robbins, T.W., Sahakian, B.J., 2004, Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia 29, 1363–1373. P.3.18 Mutation screening in a candidate region for schizophrenia on chromosome 20p13 O. Teltsh1 ° , K. Kanyas1 , O. Karni1 , A. Levi1 , M. Korner2 , A. Hamdan3 , B. Lerer1 , Y. Kohn1 . 1 Hadassah-Hebrew University Medical Center, Biological Psychiatry Labortory Departement of Psychiatry, Jerusalem, Israel; 2 Hebrew University, The Center for Genomic Technologies Institute of Life Sciences, Jerusalem, Israel; 3 Regional Mental Health Center, Psychiatry, Taibe, Israel Linkage and association studies in schizophrenia have repeatedly drawn attention to several chromosomal regions and to genes within them. The use of rare pedigrees, where genes with a major effect causes the disorder, has been proven beneficial in studies of other complex disorders. Our objective was to use this advantage by performing a genome wide linkage analysis for schizophrenia in a large, multiplex pedigree identified while studying a homogenous Arab population in Israel [1]. Previously we studied 346 microsatellite markers in 24 pedigree members affected with schizophrenia spectrum disorders and 32 unaffected relatives and found evidence for linkage on chromosome 20p13. We identified a haplotype of 3 markers, 1.8 Mb in length, which was found to be shared by most affected pedigree members. This genomic region contains strong candidate genes for schizophrenia − OXT, AVP, PANK2 and ATRN [2]. The current study focuses on mutation screening of these 4 genes. Sequencing included all exons and UTRs as well as intronic regions of OXT and AVP. We sequenced three individuals. Two of them (750300 and 750401) are
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affected members of the family who carry the shared haplotype and the third (721403) is a healthy man which is not genetically related to the family and does not carry the haplotype. Since the individual 750300 is heterozygote for this haplotype and 750401 is homozygote our aim was to find a genetic variant that would appear with one copy in individual 750300, two copies in 750401 and none at all in 750401. In order to sequence these regions we amplified more than 70 different fragments. Genotypes of five SNPs within the sequence of OXT and AVP were found to be in accordance with the expected mode of inheritance. Thus, they could be associated with disease in this pedigree. Two SNP’s in the first and second introns of OXT were discovered while sequencing this gene. These SNPs seem to be rare since we did not find any data regarding the frequency of their alleles in the general population. Likewise, we also discovered two known SNPs in the first intron of AVP and a new and unknown SNP in its second intron. The hormones encoded by these genes, oxytocin and vasopressin, are known to be involved in social behavior in rodents and humans. Evidence exists for their association with other psychiatric disorders such as OCD and autism. AVP knockout mice show disturbed pre-pulse inhibition, similar to patients with schizophrenia. Our sequencing results support the possibility that OXT and/or AVP are involved in the etiology of schizophrenia. Since the SNPs we discovered are intronic, we assume that they have a regulatory effect on the expression of these genes. Another explanation is the existence of other SNPs in the regulatory regions, which may be in Linkage Disequilibrium (LD) with the identified SNPs. We are currently studying the prevalence of these rare SNPs in larger samples of patients and controls and their possible effect on expression of the genes. Further results of these studies will be presented. Reference(s) [1] Lerer, B., Segman, R.H., Hamdan, A., Kanyas, K., Karni, O., Kohn, Y., Korner, M., Lanktree, M., Kaadan, M., Turetsky, N., Yakir, A., Kerem, B., Macciardi, F., 2003, Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 8(5): 488–498. [2] Teltsh, O., Kanyas, K., Karni, O., Levi, A., Korner, M., Ben-Asher, E., Lancet, D., Hamdan, A., Lerer, B., Kohn, Y., 2007, Genome-wide linkage scan, fine mapping, and haplotype analysis in a large, inbred, Arab Israeli pedigree suggest a schizophrenia susceptibility locus on chromosome 20p13. Am J Med Genet B Neuropsychiatr Genet 147B(2): 209–215.
Clinical neuropsychopharmacology
favour to patients receiving oxcarbazepine treatment (0.33±6.02 and 4.00±7.30 respectively, p = 0.0688). No differences were found between the groups in the BISCognitive (p = 0.4494) and BIS-Impulsiveness subscales (p = 0.1786). Scores for secondary efficacy such as CGI and HAMA did not show difference between both groups at endpoint. Although without statistically significant difference between the groups, higher GAF score was observed in the oxcarbazepine group at final visit (2.37±12.57 and −1.48±15.31; p = 0.077). Conclusion: To our knowledge, this is the first placebo-controlled, randomized clinical trials showing the superiority of adjunctive treatment of oxcarbazepine over placebo in the long-term treatment of impulsivity. Our results suggest that oxcarbazepine may play a role in the treatment and prevention of impulsive-control disorders in bipolar patients. Furthermore, there was a trend for patients receiving co-therapy oxcarbazepine plus lithium towards a better functioning than patients on lithium monotherapy. Reference(s) [1] Swann, A.C., Pazzaglia, P., Nicholls, A., Dougherty, D.M., Moeller, F.G., 2003, Impulsivity and phase of illness in bipolar disorder. J Affect Disord Jan; 73(1−2): 105–111. [2] Popova, E., Leighton, C., Bernabarre, A., Bernardo, M., Vieta, E., 2007, Oxcarbazepine in the treatment of bipolar and schizoaffective disorders. Expert Rev Neurother Jun; 7(6): 617–626. [3] Vieta, E., Cruz, N., Garc´ıa-Campayo, J., de Arce, R., Manuel Crespo, J., Vall`es, V., P´erez-Blanco, J., Roca, E., Manuel Olivares, J., Mor´ın˜ igo, A., Fern´andez-Villamor, R., Comes, M., 2008, A doubleblind, randomized, placebo-controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol Jun; 11(4): 445–452. P.3.17 The effects of modafinil on cognitive and emotional functions in the first episode of psychosis L. Scoriels1 ° , J. Barnett1 , G. Murray1 , B. Sahakian1 , S. Cherukuru2 , M. Fielding2 , F. Cheng2 , P. Jones1 . 1 University of Cambridge, Psychiatry, Cambridge, United Kingdom; 2 Cambridgeshire and Peterborough Mental Heath NHS Trust, Cameo, Cambridge, United Kingdom Cognitive and emotional impairments are important determinants of functional outcome in schizophrenia. People suffering from first-episode psychosis (FEP) also
show these dysfunctions and current antipsychotic drugs do not help. Modafinil is a central nervous system wake-promoting agent indicated for the treatment of narcolepsy [1]. Previous studies have shown that modafinil can enhance mood, attention, memory and executive functions in healthy volunteers [2], schizophrenia [3] and bipolar depression. Following the research into the effects of modafinil in chronic schizophrenia, we aimed to establish the role of modafinil in the adjuvant treatment of schizophrenia in the first episode of psychotic illness, a time when strict diagnosis is often difficult to establish but when therapeutic endeavor is arguably most vital. A within-subject, randomised, double-blind, placebocontrolled crossover study is being carried out. To date, 27 patients attended on two occasions separated by at least one week. On each occasion, patients received either a single dose of 200 mg modafinil or a placebo prior to cognitive assessment. Analysis of variance (ANOVA) for repeated measures was carried out on our preliminary data and a post-hoc analysis was run for subgroups of high and low performance levels (as determined by premorbidIQ at baseline) on the basis the performance of patients with schizophrenia has known heterogeneity, drug effects may relay to their baseline levels of performance and our ANOVA revealed many significant effects of performance levels on the outcome measures.Our preliminary results on ANOVA revealed a significant improvement on the digit backward task (F(22,1) = 6.862, p = 0.016) * a measure of working memory – and a trend for improvement on the digit forward task (F(22,1) = 4.05, p = 0.057) with modafinil. Post-hoc analysis revealed that only high performers improved significantly on digit backward (F(12,1) = 7.837, p = 0.016) and had a trend for improvement on digit forward (F(12,1) = 3.782, p = 0.076) with the drug. Moreover, ANOVA measures also revealed a trend for improvement in face recognition (F(22,1) = 3.239, p = 0.086) and emotional face recognition (F(22,1) = 4.179, p = 0.053) with modafinil. Sad faces recognition were significantly improved (F(22,1) = 8.526, p = 0.008) with the drug. Post-hoc analysis showed significant improvement in face recognition for low performers (F(12,1) = 6.598, p = 0.028), but not for high performers. Whereas modafinil revealed a significant improvement in emotional face recognition (F(12,1) = 5.205, p = 0.042) for high performers, but not for low performers. Sad faces were recognized significantly better (F(12,1) = 6.885, p = 0.022) only by high performers.Modafinil improves working memory in the first episode of psychosis. This confirms the previous results found in chronic schizophrenia, with the additional information that only high performers seem to benefit from the drug. However, a new and more interesting result, is that modafinil also seems to improve face recognition in first episode psychosis patients. Low
Clinical neuropsychopharmacology performers improved their ability to recognize faces with the drug, but this improvement did not seem to be sufficient to process more complicated information, such as the discrimination of emotional faces, for which only high performers, who did not have problems in recognizing faces, improved with modafinil administration. Reference(s) [1] Minzenberg, M.J., Carter, C.S., 2008, Modafinil: A review of neurochemical actions and effects on cognition 33, 1477–1502. [2] Muller, U., Steffenhagen, N., Regenthal, R., Bublak, P., 2004, Effects of modafinil on working memory processes in humans 177: 161–169. [3] Turner, D.C., Clark, L., Pomarol-Clotet, E., McKenna, P., Robbins, T.W., Sahakian, B.J., 2004, Modafinil improves cognition and attentional set shifting in patients with chronic schizophrenia 29, 1363–1373. P.3.18 Mutation screening in a candidate region for schizophrenia on chromosome 20p13 O. Teltsh1 ° , K. Kanyas1 , O. Karni1 , A. Levi1 , M. Korner2 , A. Hamdan3 , B. Lerer1 , Y. Kohn1 . 1 Hadassah-Hebrew University Medical Center, Biological Psychiatry Labortory Departement of Psychiatry, Jerusalem, Israel; 2 Hebrew University, The Center for Genomic Technologies Institute of Life Sciences, Jerusalem, Israel; 3 Regional Mental Health Center, Psychiatry, Taibe, Israel Linkage and association studies in schizophrenia have repeatedly drawn attention to several chromosomal regions and to genes within them. The use of rare pedigrees, where genes with a major effect causes the disorder, has been proven beneficial in studies of other complex disorders. Our objective was to use this advantage by performing a genome wide linkage analysis for schizophrenia in a large, multiplex pedigree identified while studying a homogenous Arab population in Israel [1]. Previously we studied 346 microsatellite markers in 24 pedigree members affected with schizophrenia spectrum disorders and 32 unaffected relatives and found evidence for linkage on chromosome 20p13. We identified a haplotype of 3 markers, 1.8 Mb in length, which was found to be shared by most affected pedigree members. This genomic region contains strong candidate genes for schizophrenia − OXT, AVP, PANK2 and ATRN [2]. The current study focuses on mutation screening of these 4 genes. Sequencing included all exons and UTRs as well as intronic regions of OXT and AVP. We sequenced three individuals. Two of them (750300 and 750401) are
S77
affected members of the family who carry the shared haplotype and the third (721403) is a healthy man which is not genetically related to the family and does not carry the haplotype. Since the individual 750300 is heterozygote for this haplotype and 750401 is homozygote our aim was to find a genetic variant that would appear with one copy in individual 750300, two copies in 750401 and none at all in 750401. In order to sequence these regions we amplified more than 70 different fragments. Genotypes of five SNPs within the sequence of OXT and AVP were found to be in accordance with the expected mode of inheritance. Thus, they could be associated with disease in this pedigree. Two SNP’s in the first and second introns of OXT were discovered while sequencing this gene. These SNPs seem to be rare since we did not find any data regarding the frequency of their alleles in the general population. Likewise, we also discovered two known SNPs in the first intron of AVP and a new and unknown SNP in its second intron. The hormones encoded by these genes, oxytocin and vasopressin, are known to be involved in social behavior in rodents and humans. Evidence exists for their association with other psychiatric disorders such as OCD and autism. AVP knockout mice show disturbed pre-pulse inhibition, similar to patients with schizophrenia. Our sequencing results support the possibility that OXT and/or AVP are involved in the etiology of schizophrenia. Since the SNPs we discovered are intronic, we assume that they have a regulatory effect on the expression of these genes. Another explanation is the existence of other SNPs in the regulatory regions, which may be in Linkage Disequilibrium (LD) with the identified SNPs. We are currently studying the prevalence of these rare SNPs in larger samples of patients and controls and their possible effect on expression of the genes. Further results of these studies will be presented. Reference(s) [1] Lerer, B., Segman, R.H., Hamdan, A., Kanyas, K., Karni, O., Kohn, Y., Korner, M., Lanktree, M., Kaadan, M., Turetsky, N., Yakir, A., Kerem, B., Macciardi, F., 2003, Genome scan of Arab Israeli families maps a schizophrenia susceptibility gene to chromosome 6q23 and supports a locus at chromosome 10q24. Mol Psychiatry 8(5): 488–498. [2] Teltsh, O., Kanyas, K., Karni, O., Levi, A., Korner, M., Ben-Asher, E., Lancet, D., Hamdan, A., Lerer, B., Kohn, Y., 2007, Genome-wide linkage scan, fine mapping, and haplotype analysis in a large, inbred, Arab Israeli pedigree suggest a schizophrenia susceptibility locus on chromosome 20p13. Am J Med Genet B Neuropsychiatr Genet 147B(2): 209–215.