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P.3.c.005 Clozapine and expression of the neurodevelopmental genes: a pilot study
P.3.c. Psychotic disorders and treatment − Treatment (basic) P.3.c.004 Blood levels of glucose and insulin, insulin resistance and body composition in patients with schizophrenia on clozapine monotherapy A. Wysokinski1 ° 1 Medical University of Lodz, Department of Old Age Psychiatry and Psychotic Disorders, Lodz, Poland Objective: We tested the hypothesis that blood glucose and insulin levels are higher in schizophrenic subjects on clozapine monotherapy than in healthy control and they correlate with anthropometric measurements, laboratory tests and results of bioimpedance analysis of body composition. Methods: Data for 24 subjects with schizophrenia treated with clozapine and 24 age-, sex- and fat mass index-matched healthy volunteers was analysed. Results: For group of patients treated with clozapine the mean age was 38.8±12.6 and 39.9±12.3 for the control group (p = 0.62). In both groups there were 12 men and 12 women. The mean duration of monotherapy with clozapine was 131.8±114.3 months and mean clozapine dose was 341.1±148.6 mg/day. We have found no inter-group differences for body composition analysis. Lean body mass was higher in men in the whole study sample (60.1±6.4 vs. 43.8±5.4 kg, p < 0.001) and in the clozapine group (59.6±5.7 vs. 45.3±7.0 kg, p < 0.001). Similarly, basal metabolic rate was higher in men in the whole study sample (1707.7±182.3 vs. 1337.3±138.4 kg, p < 0.001) and in the clozapine group (1701.2±138.2 vs. 1362.7±173.0 kg, p < 0.001). In the clozapine group fasting glucose levels correlated with clozapine dose (R = −0.43, p = 0.03), HOMA1-IR (R = 0.64, p < 0.001) and QUICKI (R = −0.64, p < 0.001), while fasting insulin levels correlated with weight (R = 0.66, p < 0.001), BMI (R = 0.54, p = 0.007), abdominal circumference (R = 0.53, p = 0.007), waist circumference (R = 0.43, p = 0.04), total body fat [kg] (R = 0.51, p = 0.01), uric acid (R = 0.50, p = 0.01), HOMA1IR (R = 0.86, p < 0.001), HOMA2-IR (R = 0.99, p < 0.001) and QUICKI (R = −0.86, p < 0.001). Patients taking clozapine had higher fasting levels of glucose (103.5±31.6 vs. 87.8±11.7 mg/dL, p = 0.04). There was no difference for fasting insulin concentrations between clozapine and control group (11.8±8.2 vs. 7.6±3.2 mU/mL, p = 0.08), HOMA1-IR between clozapine and control group (3.3±3.4 vs. 1.7±0.8, p = 0.06), HOMA2-IR between clozapine and control group (1.6±1.1 vs. 1.0±0.4, p = 0.06) and QUICKI between clozapine and control group (0.15±0.01 vs. 0.16±0.01, p = 0.06). In the clozapine group blood insulin levels were lower in subjects with BMI <25 kg/m2 comparing to subjects with BMI 25 kg/m2 (7.0±3.3 vs. 13.4±8.8 mU/mL, p = 0.04) and in subjects without abdominal obesity comparing to subjects with abdominal obesity (6.3±2.4 vs. 13.3±8.6 mU/mL, p = 0.03). There were no significant differences between smokers and non-smokers (p = 0.25), subjects with total body fat lower and higher than target maximum based on BIA (p = 0.28), without and with dyslipidemia (p = 0.85). For blood glucose levels, in the clozapine group there were no significant differences between smokers and non-smokers (p = 0.97), subjects with total body fat lower and higher than target maximum based on BIA (p = 0.59), subjects with BMI <25 kg/m2 and 25 kg/m2 (p = 0.87), without abdominal obesity and with abdominal obesity (p = 0.50), without and with dyslipidemia (p = 0.70). Conclusions: We found higher blood glucose levels in subjects taking clozapine and no differences in blood insulin levels
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between subjects with schizophrenia and controls. Association between blood insulin levels and abdominal/waist circumferences support central obesity role as an important risk factor of insulin resistance.
P.3.c.005 Clozapine and expression of the neurodevelopmental genes: a pilot study M.S. Karbownik1 ° , J. Szemraj2 , L. Wieteska2 , M. Panek3 , L. Mokros4 , M. Michalik4 , T. Pietras5 1 Medical University of Lodz, Department of Pharmacology and Toxicology, Lodz, Poland; 2 Medical University of Lodz, Department of Medical Biochemistry, Lodz, Poland; 3 Medical University of Lodz, Department of Internal Medicine Asthma and Allergy, Lodz, Poland; 4 Medical University of Lodz, Medical Student, Lodz, Poland; 5 Medical University of Lodz, Department of Pneumology and Allergology, Lodz, Poland Introduction: Clozapine is one of the most effective antipsychotic drugs, often referred to as the gold standard in the treatment of schizophrenia. Apart from traditionally recognized mechanism of action (blocking dopamine D2 and serotonin 5-HT2A receptors), clozapine has been suggested to affect the expression of genes encoding the neurodevelopmental signaling molecules: neuregulin 1 (NRG1), one of its receptors ErbB4 (ERBB4), and two subunits of downstream class IA phosphoinositide-3-kinase (PIK3CD, PIK3R3), recently recognized as schizophrenia susceptibility genes [1]. Aim of the study: The aim of the study was to examine the effect of clozapine on the mRNA expression of genes encoding the NRG1-downstream molecules ERBB4, PIK3CD, PIK3R3, and the negative modulator of the kinase, PTEN . Materials and Methods: U-87MG human glioblastoma cell line was used as an experimental model. The cells were incubated with or without clozapine in the concentration of 5 mM and 25 mM for 24 hours. Thiazolyl blue tetrazolium bromide viability assay was used to ensure non-toxicity of clozapine. Real-time quantitative polymerase chain reaction followed by DCT analysis was used to examine the effect of clozapine on the mRNA expression of the genes. GAPDH gene, encoding glyceraldehyde 3-phosphate dehydrogenase, was used as a house-keeping reference gene. The data was analyzed by the Student’s t-test. Results and Discussion: Clozapine in the 5−25 mM concentration range is non-toxic to U-87MG cells after twenty-four hours of incubation (data not shown). Although 5 mM clozapine does not affect the expression of any of the tested genes, 25 mM clozapine increases the mRNA expression of ERBB4 1.8-fold, PIK3CD 3.2-fold, PIK3R3 6.2-fold, and PTEN 2.4-fold (Table). Therapeutically feasible concentration of clozapine that the central nervous system cells are exposed to is difficult to predict and establish, however, the concentration of 25 mM may be reached in clinical settings, suggesting clinical relevance of our findings. Until now, there has been only one study reporting the effect of clozapine on the expression of ERBB4 protein product in an animal model [2]. We found no data on the expression of the remaining genes. However, taking together, our results remain in accordance with the overall trend in the genes expression observed after exposure to various antipsychotic agents [1,3]. Conclusions: Clozapine seems to exhibit a new mechanism of action. In the glioblastoma cell line, at the concentration of
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P.3.c. Psychotic disorders and treatment − Treatment (basic)
25 mM, the drug increases the mRNA expression of the genes encoding the molecules involved in the neuregulin 1-ErbB4-PI3K signaling pathway. The mechanism by which clozapine increases the expression of the genes remains unknown. The paper presents the preliminary results of the study. Table: Fold change in the tested genes expression shown as 2−DDCT a . Standard deviations (SD) and p-values are also given. Gene tested
Fold change in the tested genes expression Clozapine 25 mM Clozapine 5 mM Fold change p Fold change p
ERBB4 PIK3CD PIK3R3 PTEN
1.84±0.39 3.19±0.33 6.28±0.65 2.36±0.62
a
DDCT = DCT,
clozapine
− DCT,
0.0082 0.0000 0.0000 0.0017
1.05±0.11 1.04±0.19 1.55±0.21 1.17±0.15
0.7975 0.9076 0.1350 0.2437
control .
References [1] Law, A.J., Wang, Y., Sei, Y., O’Donnell, P., Piantadosi, P., et al., 2012. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110d inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A 109, 12165–12170. [2] Wang, X.D., Su, Y.A., Guo, C.M., Yang, Y., Si, T.M., 2008. Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol 11, 553–561. [3] Pan, B., Huang, X.F., Deng, C., 2011. Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35, 924–930.
P.3.c.006 Effectiveness of paliperidone depot in violent men with co-morbid schizophrenia and dissocial personality disorder R. Mitra1 ° , M. Das1 , F. Larkin1 , C. Ross1 , J. Romero-Urcelay1 1 Broadmoor Hospital, Mental Illness, Crowthorne, United Kingdom Purpose of the study: Paliperidone is licensed as both oral and depot antipsychotic medication for the treatment of schizophrenia. It is a metabolite of risperidone for which there is robust evidence for treatment in schizophrenia. When compliance is a problem for forensic patients often with treatment resistant schizophrenia and poor insight, a depot antipsychotic is a useful option. There is evidence paliperidone is well tolerated with similar efficacy to the risperidone depot but it also has additional practical advantages including a faster onset of action, a smaller needle making it more patient friendly and fewer monthly injections. Whilst there is data for the effectiveness of paliperidone, there is no report for forensic patients and those with co-morbid Personality Disorders. We report a case series of our experience with paliperidone depot in five patients within a UK high secure hospital. All these patients had diagnoses of schizophrenia and Dissocial Personality Disorder and were admitted with histories of violence alongside psychotic symptoms. We evaluated the clinical effectiveness of paliperidone depot and its effect on violence, aggression and personality pathology. Methods: Anonymised patient records were used to formulate Clinical Global Impression (CGI) scores and find incidents of violence and aggression. We looked at the effect on specific personality disorder symptom clusters (Cognitive-Perceptual, ImpulsiveBehavioural dyscontrol and Affective dysregulation) plus their individual engagement in occupational and psychological therapies.
Metabolic parameters including Body Mass Index, glucose and cholesterol as well as prolactin levels were monitored. Results: All five patients showed improvement on the paliperidone depot; there was a significant improvement in the CGI scores plus benefits for patients in the three symptom domains. The three patients that had violent or aggressive incidents in the six months preceding the commencement of the paliperidone, all had a 50% reduction in the number of incidents recorded compared to the six months after. There was no significant effect on any of the metabolic parameters monitored although hyperprolactinaemia (albeit asymptomatic) is a problem. Four of the patients on the depot for longer than 6 months showed improvement in occupational therapy and psychological work engagement. Conclusions: We found in our case series that paliperidone depot was effective in reducing symptoms of schizophrenia and report for the first time that it was also effective in reducing violence and aggression as well as improving personality pathology dimensions in a co-morbid patient. A depot antipsychotic effective in reducing violence in addition to improving psychotic symptoms is significant and promising for the future management of high secure forensic patients. Given the number of patients, this study, as a case series evaluation, should primarily considered as exploratory. Further studies are required over a longer period of time to build up more robust data on the efficacy of this medication and its role in reducing violent behaviour in a High Secure setting.
P.3.c.007 Challenges in treating children and adolescents with antipsychotic agents A. Simion1 ° , A. Crasan2 , D. Calin1 , M. Muscalu1 , S. Macovei1 Dr. Al. Obregia” Psychiatry Hospital, Child and Adolescent Department, Bucharest, Romania; 2 “Prof. Dr. Al. Obregia” Psychiatry Hospital, Adult Psychiatry Department, Bucharest, Romania 1 “Prof.
Background: Antipsychotic agents are currently employed in the treatment of a great number of psychiatric disorders that affect children and adolescents such as schizophrenia, acute psychotic episodes, bipolar disorder, OCD, severe depression, anxiety disorders, eating disorders and tic disorders. Some of the most commonly used antipsychotic agents used in the treatment of these disorders are olanzapine, aripiprazole, risperidone, quetiapine, levomepromazine and haloperidol [1]. While being of great benefit to the patient, these agents have some restrictive side effects such as weight gain, hiperprolactinemia, extrapyramidal side-effects (dystonia or Parkinsonian movements), sedation or somnolence, neutropenia or agranulocytosis. Objectives: In this analysis we try to identify the main obstacles in administering antipsychotic agents to children and adolescents and also to discuss how best to avoid these obstacles from the initial stages of the treatment and even in later ones. Methods: We have studied several case reports of children admitted to the Child and Adolescent Department ‘Prof. Dr. Alexandru Obregia’ Psychiatric Hospital in Bucharest who have received treatment with antipsychotic agents and were monitored at the clinic for a period of at least 6 months after treatment initiation. Results: We have identified several main factors that exert influence on treatment adherence and, as such, on treatment efficiency. These are both related to the agent itself, such as the appropriateness of a specific agent for treating a certain disorder
S517
between subjects with schizophrenia and controls. Association between blood insulin levels and abdominal/waist circumferences support central obesity role as an important risk factor of insulin resistance.
P.3.c.005 Clozapine and expression of the neurodevelopmental genes: a pilot study M.S. Karbownik1 ° , J. Szemraj2 , L. Wieteska2 , M. Panek3 , L. Mokros4 , M. Michalik4 , T. Pietras5 1 Medical University of Lodz, Department of Pharmacology and Toxicology, Lodz, Poland; 2 Medical University of Lodz, Department of Medical Biochemistry, Lodz, Poland; 3 Medical University of Lodz, Department of Internal Medicine Asthma and Allergy, Lodz, Poland; 4 Medical University of Lodz, Medical Student, Lodz, Poland; 5 Medical University of Lodz, Department of Pneumology and Allergology, Lodz, Poland Introduction: Clozapine is one of the most effective antipsychotic drugs, often referred to as the gold standard in the treatment of schizophrenia. Apart from traditionally recognized mechanism of action (blocking dopamine D2 and serotonin 5-HT2A receptors), clozapine has been suggested to affect the expression of genes encoding the neurodevelopmental signaling molecules: neuregulin 1 (NRG1), one of its receptors ErbB4 (ERBB4), and two subunits of downstream class IA phosphoinositide-3-kinase (PIK3CD, PIK3R3), recently recognized as schizophrenia susceptibility genes [1]. Aim of the study: The aim of the study was to examine the effect of clozapine on the mRNA expression of genes encoding the NRG1-downstream molecules ERBB4, PIK3CD, PIK3R3, and the negative modulator of the kinase, PTEN . Materials and Methods: U-87MG human glioblastoma cell line was used as an experimental model. The cells were incubated with or without clozapine in the concentration of 5 mM and 25 mM for 24 hours. Thiazolyl blue tetrazolium bromide viability assay was used to ensure non-toxicity of clozapine. Real-time quantitative polymerase chain reaction followed by DCT analysis was used to examine the effect of clozapine on the mRNA expression of the genes. GAPDH gene, encoding glyceraldehyde 3-phosphate dehydrogenase, was used as a house-keeping reference gene. The data was analyzed by the Student’s t-test. Results and Discussion: Clozapine in the 5−25 mM concentration range is non-toxic to U-87MG cells after twenty-four hours of incubation (data not shown). Although 5 mM clozapine does not affect the expression of any of the tested genes, 25 mM clozapine increases the mRNA expression of ERBB4 1.8-fold, PIK3CD 3.2-fold, PIK3R3 6.2-fold, and PTEN 2.4-fold (Table). Therapeutically feasible concentration of clozapine that the central nervous system cells are exposed to is difficult to predict and establish, however, the concentration of 25 mM may be reached in clinical settings, suggesting clinical relevance of our findings. Until now, there has been only one study reporting the effect of clozapine on the expression of ERBB4 protein product in an animal model [2]. We found no data on the expression of the remaining genes. However, taking together, our results remain in accordance with the overall trend in the genes expression observed after exposure to various antipsychotic agents [1,3]. Conclusions: Clozapine seems to exhibit a new mechanism of action. In the glioblastoma cell line, at the concentration of
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P.3.c. Psychotic disorders and treatment − Treatment (basic)
25 mM, the drug increases the mRNA expression of the genes encoding the molecules involved in the neuregulin 1-ErbB4-PI3K signaling pathway. The mechanism by which clozapine increases the expression of the genes remains unknown. The paper presents the preliminary results of the study. Table: Fold change in the tested genes expression shown as 2−DDCT a . Standard deviations (SD) and p-values are also given. Gene tested
Fold change in the tested genes expression Clozapine 25 mM Clozapine 5 mM Fold change p Fold change p
ERBB4 PIK3CD PIK3R3 PTEN
1.84±0.39 3.19±0.33 6.28±0.65 2.36±0.62
a
DDCT = DCT,
clozapine
− DCT,
0.0082 0.0000 0.0000 0.0017
1.05±0.11 1.04±0.19 1.55±0.21 1.17±0.15
0.7975 0.9076 0.1350 0.2437
control .
References [1] Law, A.J., Wang, Y., Sei, Y., O’Donnell, P., Piantadosi, P., et al., 2012. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110d inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A 109, 12165–12170. [2] Wang, X.D., Su, Y.A., Guo, C.M., Yang, Y., Si, T.M., 2008. Chronic antipsychotic drug administration alters the expression of neuregulin 1beta, ErbB2, ErbB3, and ErbB4 in the rat prefrontal cortex and hippocampus. Int J Neuropsychopharmacol 11, 553–561. [3] Pan, B., Huang, X.F., Deng, C., 2011. Antipsychotic treatment and neuregulin 1-ErbB4 signalling in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 35, 924–930.
P.3.c.006 Effectiveness of paliperidone depot in violent men with co-morbid schizophrenia and dissocial personality disorder R. Mitra1 ° , M. Das1 , F. Larkin1 , C. Ross1 , J. Romero-Urcelay1 1 Broadmoor Hospital, Mental Illness, Crowthorne, United Kingdom Purpose of the study: Paliperidone is licensed as both oral and depot antipsychotic medication for the treatment of schizophrenia. It is a metabolite of risperidone for which there is robust evidence for treatment in schizophrenia. When compliance is a problem for forensic patients often with treatment resistant schizophrenia and poor insight, a depot antipsychotic is a useful option. There is evidence paliperidone is well tolerated with similar efficacy to the risperidone depot but it also has additional practical advantages including a faster onset of action, a smaller needle making it more patient friendly and fewer monthly injections. Whilst there is data for the effectiveness of paliperidone, there is no report for forensic patients and those with co-morbid Personality Disorders. We report a case series of our experience with paliperidone depot in five patients within a UK high secure hospital. All these patients had diagnoses of schizophrenia and Dissocial Personality Disorder and were admitted with histories of violence alongside psychotic symptoms. We evaluated the clinical effectiveness of paliperidone depot and its effect on violence, aggression and personality pathology. Methods: Anonymised patient records were used to formulate Clinical Global Impression (CGI) scores and find incidents of violence and aggression. We looked at the effect on specific personality disorder symptom clusters (Cognitive-Perceptual, ImpulsiveBehavioural dyscontrol and Affective dysregulation) plus their individual engagement in occupational and psychological therapies.
Metabolic parameters including Body Mass Index, glucose and cholesterol as well as prolactin levels were monitored. Results: All five patients showed improvement on the paliperidone depot; there was a significant improvement in the CGI scores plus benefits for patients in the three symptom domains. The three patients that had violent or aggressive incidents in the six months preceding the commencement of the paliperidone, all had a 50% reduction in the number of incidents recorded compared to the six months after. There was no significant effect on any of the metabolic parameters monitored although hyperprolactinaemia (albeit asymptomatic) is a problem. Four of the patients on the depot for longer than 6 months showed improvement in occupational therapy and psychological work engagement. Conclusions: We found in our case series that paliperidone depot was effective in reducing symptoms of schizophrenia and report for the first time that it was also effective in reducing violence and aggression as well as improving personality pathology dimensions in a co-morbid patient. A depot antipsychotic effective in reducing violence in addition to improving psychotic symptoms is significant and promising for the future management of high secure forensic patients. Given the number of patients, this study, as a case series evaluation, should primarily considered as exploratory. Further studies are required over a longer period of time to build up more robust data on the efficacy of this medication and its role in reducing violent behaviour in a High Secure setting.
P.3.c.007 Challenges in treating children and adolescents with antipsychotic agents A. Simion1 ° , A. Crasan2 , D. Calin1 , M. Muscalu1 , S. Macovei1 Dr. Al. Obregia” Psychiatry Hospital, Child and Adolescent Department, Bucharest, Romania; 2 “Prof. Dr. Al. Obregia” Psychiatry Hospital, Adult Psychiatry Department, Bucharest, Romania 1 “Prof.
Background: Antipsychotic agents are currently employed in the treatment of a great number of psychiatric disorders that affect children and adolescents such as schizophrenia, acute psychotic episodes, bipolar disorder, OCD, severe depression, anxiety disorders, eating disorders and tic disorders. Some of the most commonly used antipsychotic agents used in the treatment of these disorders are olanzapine, aripiprazole, risperidone, quetiapine, levomepromazine and haloperidol [1]. While being of great benefit to the patient, these agents have some restrictive side effects such as weight gain, hiperprolactinemia, extrapyramidal side-effects (dystonia or Parkinsonian movements), sedation or somnolence, neutropenia or agranulocytosis. Objectives: In this analysis we try to identify the main obstacles in administering antipsychotic agents to children and adolescents and also to discuss how best to avoid these obstacles from the initial stages of the treatment and even in later ones. Methods: We have studied several case reports of children admitted to the Child and Adolescent Department ‘Prof. Dr. Alexandru Obregia’ Psychiatric Hospital in Bucharest who have received treatment with antipsychotic agents and were monitored at the clinic for a period of at least 6 months after treatment initiation. Results: We have identified several main factors that exert influence on treatment adherence and, as such, on treatment efficiency. These are both related to the agent itself, such as the appropriateness of a specific agent for treating a certain disorder