- Email: [email protected]
Poster #M5 CLOZAPINE-INDUCED SEIZURES, EEG ABNORMALITIES, AND CLINICAL RESPONSE IN JAPANESE PATIENTS WITH SCHIZOPHRENIA
S190
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
*CRLA-SG Collaborators: Vesile Altınyazar, Memduha Aydın, Berna B. Kıvırcık Akdede, Köksal Alptekin, Aysen ¸ Esen Danacı, Bilge Çetin I˙ lhan, Semra Ulusoy, Haldun Soygür, Hatice Özdemir, Mustafa Çelik, Fatma Özlem Orhan, Hasret Ozan, I˙ smet Kaygısız
Poster #M3 PREDICTION OF SUICIDAL BEHAVIOURS IN YOUNG PEOPLE PRESENTING WITH FIRST-EPISODE PSYCHOSIS IN HONG KONG: A 3-YEAR FOLLOW-UP STUDY Sze Man Chen, W.C. Chang, L.M. Hui, K.W. Chan, H.M. Lee, Eric Y.H. Chen The University of Hong Kong Background: Suicide behaviours are common in the early stage of psychotic disorders. The present study aimed to examine the rate and predictors of suicidal behaviours in the initial 3 years of treatment for patients presenting with first-episode psychosis to a territory-wide specialized early intervention program, namely EASY (Early Assessment Service for Young people with psychosis) in Hong Kong. Methods: Seven hundred patients aged 15-25 years presenting with firstepisode psychosis (based on ICD-10 criteria) to EASY program between July 2001 and August 2003 were included in the study. Of the initial cohort, 546 completed the 3-year follow-up and thus constituted the final study sample. Demographics, past history of suicidal attempts, substance abuse, baseline and follow-up clinical and functioning variables were collected via systematic medical record review based on standardized protocol. Suicidal behaviour was defined as either attempted or committed suicide. A series of univariate logistic regression analyses were performed to examine the relationship of suicidal behaviour (yes/no in 3-year follow-up) with potential predictor variables, followed by multivariate regression model to determine independent predictors of suicidal behaviours. Results: There were no significant differences between completers and non-completers in socio-demographics, past suicidal attempt, baseline clinical and functional measures with the exception that completers were significantly more likely to have schizophrenia diagnosis. By the end of 3-year follow-up, 11.2% (n=61) of patients exhibited suicidal behaviour over the study period, including 1.3% (n=7) committing suicide. Univariate analyses revealed that hospitalization at intake (OR=0.45, p<0.05), past history of substance abuse (OR=0.43, p<0.05), pre-treatment suicidal attempt (OR=0.38, p<0.01), and baseline social functioning (OR=0.97, p<0.01) were identified as the risk factors for suicidal behaviours. Multivariate regression demonstrated that only pre-treatment suicidal attempt, past history of substance abuse and baseline functioning independently predicted the occurrence of suicidal behaviours during 3-year follow-up period (Nagelkerke R2 = 0.064, chi-square= 21.8, p<0.0001). Discussion: In a large representative cohort of Chinese young patients with first-episode psychosis, we found that 3-year prevalence rate for suicidal behaviours and suicide was 11.2% and 1.3%, respectively. Pre-treatment suicidal attempt, past history of substance abuse and baseline functioning were shown to independently predict suicidal behaviours in the initial 3 years of treatment for first-episode psychosis in EASY program.
Poster #M4 TREATMENT OF CLOZAPINE-INDUCED HYPERSALIVATION WITH AMISULPRIDE: A SYSTEMATIC REVIEW Maria Cristina R. Grilli-Tissot 1 , M.R. Louzã 2 1 Clínica Greenwood; 2 Instituto de Psiquiatria do Hospital das Clinicas da FMUSP Background: Clozapine is an atypical antipsychotic indicated for treatment resistant schizophrenia. Hypersalivation is a frequent and bothersome side effect, leading to social withdrawal and potentially life-threating situations (e.g., choking, aspiration pneumonia). Several treatments are proposed for clozapine-induced sialorrhea, including atropine, botulinum, biperiden among others. Amisulpride is a benzamide derivate with high affinity on D2/D3 receptors, similar to sulpiride which is reported to be an option in sialohrrea treatment. Methods: A systematic review of the treatment of clozapine induced hypersalivation (CIH) with amisulpride. Medline and Embase were researched
with the search terms “clozapine”, “amisulpride”, “hypersalivation”, or “sialorrhea”. No language- or publication date restriction. Results: A total of 296 abstracts were found. After exclusion of duplicates, 6 abstracts remained. These were fully read by both authors, to obtain relevant data. Four were case reports, 2 were RCTs, one against placebo and one comparing amisulpride with moclobemide. In all reports (case reports and RCTs) there was a reduction of sialorrhea with amisulpride. This drug also showed additional benefits in reducing symptoms as measured by the PANSS. Discussion: Hypersalivation is a frequent and unpleasant side effect that interferes in the adherence to treatment by the patients. As the pathophysiology of clozapine mechanism of hypersalivation remains unclear, possibly involving both cholinergic and adrenergic receptors, different types of drugs have been tried, but their effectiveness is controversial. Other explanations include an interference in the mechanism of swallowing and an alteration in circadian rhythm with increased salivation at night. The perception of the amisulpride effects on CIH is evidenced in 4 published case reports. During the last few years, there have been 2 RCT that confirmed the reports, and associated with additional benefits on symptoms treatment, showing an increasing of interest in this drug action. However, the pathophysiology of amisulpride hypo salivation caused by clozapine use is still unknown. In experiments with rodents, no clear evidence of its effects was observed. Amisulpride, per se, caused no flow of saliva, had no effect on blood flow and there was no support for any inhibitory action at central level, but potentiated the actions of agonists by mobilizing intracellular pathways, supporting the view that amisulpride acts at gland level. In fact, in a posterior study, amisulpride induced ultrastructural signs of secretory activity, hypothesizing that may provide an overall readiness for secretion, resulting in augmented responses to agonists, contrasting with the clinical observations. In another hand, amisulpride, as an atypical antipsychotic alone, appears in the first line treatment of schizophrenia (Harvard Project, Osser DN, 2013) and a recent meta-analysis showed that is effective in partial responders when associated with clozapine (Porcelli, 2012; Pani, 2008). Additionally, it has been suggested that this combination could permit a decrease of the amount of clozapine use, reducing dose-dependent sideeffects. (plasma clozapine concentration >0.25 mg/l increase the chances of appearance of side effects). Although amisulpride, because of its profile in enhance therapeutic use of clozapine and it’s a well tolerated drug, seems to be an interesting option on treating sialohrrea, there is only a small studies to confirm this initial observation and, until know, the experimental findings in rats are unexpectedly against clinical experience.
Poster #M5 CLOZAPINE-INDUCED SEIZURES, EEG ABNORMALITIES, AND CLINICAL RESPONSE IN JAPANESE PATIENTS WITH SCHIZOPHRENIA Yuka S. Kikuchi 1,2 , Wataru Sato 3 , Keiichiro Ataka 3 , Kiwamu Yagisawa 3 , Yuki Omori 3 , Takashi Kanbayashi 3 , Tetsuo Shimizu 3 1 Department of Neuropsychiatry; 2 Akita University Graduate School of Medicine; 3 Department of Neuropsychiatry, Akita University Graduate School of Medicine Background: Clozapine is effective against treatment-resistant schizophrenia and was introduced to Japan in 2009. Clozapine-induced seizures are more frequent than agranulocytosis (Karper et al., 1992), and electroencephalography (EEG) abnormalities are even more common. Because clozapine efficacy varies among individuals and races, there is a need to determine the predictive factor of treatment-response and side effects of clozapine in a Japanese population to establish safe treatment practices. Here, we describe EEG abnormalities and seizures associated with clozapine treatment in Japanese schizophrenia and compare EEG results and total score of positive and negative syndrome scale (PANSS (T)) before and after treatment. Methods: Twenty patients with treatment-resistant schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria were enrolled in this study, including 4 males and 16 females. Their average age was 34 years old. EEGs were obtained prior to clozapine treatment, when seizures occurred, and every 4 weeks. PANSS (T) were used to determine clozapine treatment outcome and were compared at baseline and last observation. Results: All patients had normal baseline EEGs, and 10 patients (50%) later
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
showed EEG abnormalities. There were no significant differences between the EEG normal and EEG abnormal groups in mean age, gender, mean clozapine dose, or length of treatment with clozapine. Six patients (30%) experienced seizures; one with both tonic-clonic and myoclonic, one with tonic-clonic and four with myoclonic seizures. The mean baseline PANSS (T) scores were not significantly different between the EEG normal and EEG abnormal groups, but the mean score in the EEG abnormal group was significantly lower than that in the EEG normal group at the final follow-up. The response rate was not significantly different between the two groups. Discussion: The incidence of seizure in this study was higher than other reports in the literature. These results suggest that clozapine is more likely to cause seizures in the Japanese population. However, this study involved a small number of patients, so we cannot be certain that Japanese patients with schizophrenia have a higher risk of seizure with clozapine use; additional studies with larger samples are needed to verify our observation. All patients who experienced seizures in this study were successfully treated with valproate or lamotrigine without clozapine discontinuation. Cott (2007) described the treatment of clozapine-associated seizures with dosage reduction and/or the addition of an antiepileptic drug. It has been reported that clozapine-induced EEG abnormalities occur in a dose-dependent manner and correlated with serum level of clozapine. However, Centorrino et al. (2002) reported that clinical factors associated with EEG abnormalities included hypertension and age over 40 years old; they described no relationship between dose and EEG abnormalities. In this study, the mean dose of clozapine was no significantly different between the EEG abnormal and EEG normal groups. In half of the patients with EEG abnormalities, the clozapine dose was <300 mg. The relationship between clozapine dosage and EEG abnormality remains controversial. The baseline PANSS (T) was not significantly different between patients with normal and abnormal EEGs. However, the PANSS (T) from the last observation was significantly lower in the EEG abnormal group, indicating that EEG abnormalities appeared after clozapine treatments were associated with a good clinical response to clozapine.
Poster #M6 CARDIOMETABOLIC RISKS OF BLONANSERIN AND PEROSPIRONE IN THE MANAGEMENT OF SCHIZOPHRENIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Taro Kishi 1,2 , Yuki Matsuda 3 , Nakao Iwata 1 1 Department of Psychiatry, Fujita Health University School of Medicine; 2 PhD; 3 Department of Psychiatry,Fujita Health University school of Medicine Background: The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia. Methods: We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics. Results: In total, 4 blonanserin studies (n=1080) were identified [vs. risperidone (2 studies, n=508); vs. haloperidol (2 studies, n=572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = −0.86, 95% confidence intervals = −1.36 to −0.36, p=0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n=256), olanzapine (n=20), quetiapine (n=28), risperidone (n=53), aripiprazole (n=49), haloperidol (n=75), or mosapramine (n=81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels. Discussion: Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.
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Poster #M7 NEGATIVE SELF AND OTHER SCHEMAS AND INSECURE ATTACHMENT MEDIATE THE ASSOCIATION BETWEEN CHILDHOOD INTERPERSONAL ADVERSITY AND THE NONCLINICAL PSYCHOSIS PHENOTYPE Tamara Sheinbaum 1 , Thomas R. Kwapil 2 , Sergi Ballespí 3 , Neus Barrantes-Vidal 1,4 1 Department of Clinical and Health Psychology, Autonomous University of Barcelona; 2 Department of Psychology, University of North Carolina at Greensboro; 3 Universitat Autònoma de Barcelona; 4 Department of Mental Health, Health Foundation Sant Pere Claver (Barcelona) Background: There is mounting evidence indicating that interpersonal adversity in childhood is associated with psychotic phenomena in clinical and nonclinical populations. Among the psychological mechanisms that have been suggested to underlie this association, negative self and other schemas and insecure attachment styles have received increasing theoretical attention. However, there is scant empirical research investigating these predictions, particularly in regards to insecure attachment. The present study investigated the associations of childhood interpersonal trauma with nonclinical psychotic phenomena, and the role of negative self and other schemas and insecure attachment styles as potential mediators of the associations between early trauma exposure and nonclinical psychotic phenomena. Methods: At the initial assessment, 547 Spanish young adults completed a battery of self-report questionnaires, including measures of schizotypy, suspiciousness, psychotic-like experiences, traumatic childhood experiences, self and other schemas, and attachment style. At the second assessment, a subset of these participants (n=214), oversampled for high schizotypy and psychotic-like experiences, completed interview measures of prodromal symptoms, schizophrenia-spectrum personality disorders, childhood trauma, and attachment style. Results: At the initial assessment, physical/emotional trauma was significantly associated with positive and negative schizotypy, suspiciousness, and psychotic-like experiences. Results from the bootstrapping analyses indicated that negative self-schemas, negative other-schemas, and fearful attachment significantly mediated these associations. At the second assessment, physical/emotional trauma was significantly associated with positive and negative prodromal symptoms and schizophrenia-spectrum personality traits. Bootstrapping analyses indicated that insecure attachment was a significant mediator of these associations. Discussion: Childhood physical/emotional trauma was associated with the nonclinical psychosis phenotype across two time points and with both self-report and interview measures. These associations were mediated by theory-driven psychological mechanisms. Although the present study cannot determine causality, the findings are consistent with theoretical accounts suggesting that interpersonal childhood trauma may contribute to the formation of negative cognitive schemas and insecure attachment patterns, which, in turn, may impact upon the development and expression of the extended psychosis phenotype.
Poster #M8 POSITIVE ALLOSTERIC MODULATION OF MGLUR5 REVERSES THE AKT SIGNALING DEFICITS IN SERINE RACEMASE KNOCKOUT MICE, A GENETIC MODEL OF SCHIZOPHRENIA DUE TO NMDA RECEPTOR HYPOFUNCTION Darrick T. Balu 1,2 , Shunsuke Takagi 2 , Jose Bartolomé 3 , Thomas Steckler 3 , Carrie Jones 4 , P. Jeffrey Conn 4 , Joseph Coyle 2 1 Harvard Medical School; 2 McLean Hospital; 3 Janssen Research and Development; 4 Vanderbilt Center for Neuroscience Drug Discovery Background: There is substantial evidence that hypofunction of the Nmethyl-D-aspartate receptor (NMDAR) is a core pathophysiological mechanism underlying schizophrenia. We have previously demonstrated that serine racemase knockout (SR−/−) mice exhibit neuroanatomical and behavioral similarities to schizophrenia, as well as reductions in hippocampal Akt/glycogen synthase kinase 3 (GS3K)/mammalian target of rapamycin (mTOR) signaling that can be reversed with three weeks of D-serine treatment. Traditional metabotropic glutamate receptor 5 (mGluR5) positive allosteric modulators (PAMs) enhance NMDAR activity through circuits that are regulated by NMDARs and are currently being developed to ameliorate
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
*CRLA-SG Collaborators: Vesile Altınyazar, Memduha Aydın, Berna B. Kıvırcık Akdede, Köksal Alptekin, Aysen ¸ Esen Danacı, Bilge Çetin I˙ lhan, Semra Ulusoy, Haldun Soygür, Hatice Özdemir, Mustafa Çelik, Fatma Özlem Orhan, Hasret Ozan, I˙ smet Kaygısız
Poster #M3 PREDICTION OF SUICIDAL BEHAVIOURS IN YOUNG PEOPLE PRESENTING WITH FIRST-EPISODE PSYCHOSIS IN HONG KONG: A 3-YEAR FOLLOW-UP STUDY Sze Man Chen, W.C. Chang, L.M. Hui, K.W. Chan, H.M. Lee, Eric Y.H. Chen The University of Hong Kong Background: Suicide behaviours are common in the early stage of psychotic disorders. The present study aimed to examine the rate and predictors of suicidal behaviours in the initial 3 years of treatment for patients presenting with first-episode psychosis to a territory-wide specialized early intervention program, namely EASY (Early Assessment Service for Young people with psychosis) in Hong Kong. Methods: Seven hundred patients aged 15-25 years presenting with firstepisode psychosis (based on ICD-10 criteria) to EASY program between July 2001 and August 2003 were included in the study. Of the initial cohort, 546 completed the 3-year follow-up and thus constituted the final study sample. Demographics, past history of suicidal attempts, substance abuse, baseline and follow-up clinical and functioning variables were collected via systematic medical record review based on standardized protocol. Suicidal behaviour was defined as either attempted or committed suicide. A series of univariate logistic regression analyses were performed to examine the relationship of suicidal behaviour (yes/no in 3-year follow-up) with potential predictor variables, followed by multivariate regression model to determine independent predictors of suicidal behaviours. Results: There were no significant differences between completers and non-completers in socio-demographics, past suicidal attempt, baseline clinical and functional measures with the exception that completers were significantly more likely to have schizophrenia diagnosis. By the end of 3-year follow-up, 11.2% (n=61) of patients exhibited suicidal behaviour over the study period, including 1.3% (n=7) committing suicide. Univariate analyses revealed that hospitalization at intake (OR=0.45, p<0.05), past history of substance abuse (OR=0.43, p<0.05), pre-treatment suicidal attempt (OR=0.38, p<0.01), and baseline social functioning (OR=0.97, p<0.01) were identified as the risk factors for suicidal behaviours. Multivariate regression demonstrated that only pre-treatment suicidal attempt, past history of substance abuse and baseline functioning independently predicted the occurrence of suicidal behaviours during 3-year follow-up period (Nagelkerke R2 = 0.064, chi-square= 21.8, p<0.0001). Discussion: In a large representative cohort of Chinese young patients with first-episode psychosis, we found that 3-year prevalence rate for suicidal behaviours and suicide was 11.2% and 1.3%, respectively. Pre-treatment suicidal attempt, past history of substance abuse and baseline functioning were shown to independently predict suicidal behaviours in the initial 3 years of treatment for first-episode psychosis in EASY program.
Poster #M4 TREATMENT OF CLOZAPINE-INDUCED HYPERSALIVATION WITH AMISULPRIDE: A SYSTEMATIC REVIEW Maria Cristina R. Grilli-Tissot 1 , M.R. Louzã 2 1 Clínica Greenwood; 2 Instituto de Psiquiatria do Hospital das Clinicas da FMUSP Background: Clozapine is an atypical antipsychotic indicated for treatment resistant schizophrenia. Hypersalivation is a frequent and bothersome side effect, leading to social withdrawal and potentially life-threating situations (e.g., choking, aspiration pneumonia). Several treatments are proposed for clozapine-induced sialorrhea, including atropine, botulinum, biperiden among others. Amisulpride is a benzamide derivate with high affinity on D2/D3 receptors, similar to sulpiride which is reported to be an option in sialohrrea treatment. Methods: A systematic review of the treatment of clozapine induced hypersalivation (CIH) with amisulpride. Medline and Embase were researched
with the search terms “clozapine”, “amisulpride”, “hypersalivation”, or “sialorrhea”. No language- or publication date restriction. Results: A total of 296 abstracts were found. After exclusion of duplicates, 6 abstracts remained. These were fully read by both authors, to obtain relevant data. Four were case reports, 2 were RCTs, one against placebo and one comparing amisulpride with moclobemide. In all reports (case reports and RCTs) there was a reduction of sialorrhea with amisulpride. This drug also showed additional benefits in reducing symptoms as measured by the PANSS. Discussion: Hypersalivation is a frequent and unpleasant side effect that interferes in the adherence to treatment by the patients. As the pathophysiology of clozapine mechanism of hypersalivation remains unclear, possibly involving both cholinergic and adrenergic receptors, different types of drugs have been tried, but their effectiveness is controversial. Other explanations include an interference in the mechanism of swallowing and an alteration in circadian rhythm with increased salivation at night. The perception of the amisulpride effects on CIH is evidenced in 4 published case reports. During the last few years, there have been 2 RCT that confirmed the reports, and associated with additional benefits on symptoms treatment, showing an increasing of interest in this drug action. However, the pathophysiology of amisulpride hypo salivation caused by clozapine use is still unknown. In experiments with rodents, no clear evidence of its effects was observed. Amisulpride, per se, caused no flow of saliva, had no effect on blood flow and there was no support for any inhibitory action at central level, but potentiated the actions of agonists by mobilizing intracellular pathways, supporting the view that amisulpride acts at gland level. In fact, in a posterior study, amisulpride induced ultrastructural signs of secretory activity, hypothesizing that may provide an overall readiness for secretion, resulting in augmented responses to agonists, contrasting with the clinical observations. In another hand, amisulpride, as an atypical antipsychotic alone, appears in the first line treatment of schizophrenia (Harvard Project, Osser DN, 2013) and a recent meta-analysis showed that is effective in partial responders when associated with clozapine (Porcelli, 2012; Pani, 2008). Additionally, it has been suggested that this combination could permit a decrease of the amount of clozapine use, reducing dose-dependent sideeffects. (plasma clozapine concentration >0.25 mg/l increase the chances of appearance of side effects). Although amisulpride, because of its profile in enhance therapeutic use of clozapine and it’s a well tolerated drug, seems to be an interesting option on treating sialohrrea, there is only a small studies to confirm this initial observation and, until know, the experimental findings in rats are unexpectedly against clinical experience.
Poster #M5 CLOZAPINE-INDUCED SEIZURES, EEG ABNORMALITIES, AND CLINICAL RESPONSE IN JAPANESE PATIENTS WITH SCHIZOPHRENIA Yuka S. Kikuchi 1,2 , Wataru Sato 3 , Keiichiro Ataka 3 , Kiwamu Yagisawa 3 , Yuki Omori 3 , Takashi Kanbayashi 3 , Tetsuo Shimizu 3 1 Department of Neuropsychiatry; 2 Akita University Graduate School of Medicine; 3 Department of Neuropsychiatry, Akita University Graduate School of Medicine Background: Clozapine is effective against treatment-resistant schizophrenia and was introduced to Japan in 2009. Clozapine-induced seizures are more frequent than agranulocytosis (Karper et al., 1992), and electroencephalography (EEG) abnormalities are even more common. Because clozapine efficacy varies among individuals and races, there is a need to determine the predictive factor of treatment-response and side effects of clozapine in a Japanese population to establish safe treatment practices. Here, we describe EEG abnormalities and seizures associated with clozapine treatment in Japanese schizophrenia and compare EEG results and total score of positive and negative syndrome scale (PANSS (T)) before and after treatment. Methods: Twenty patients with treatment-resistant schizophrenia according to Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria were enrolled in this study, including 4 males and 16 females. Their average age was 34 years old. EEGs were obtained prior to clozapine treatment, when seizures occurred, and every 4 weeks. PANSS (T) were used to determine clozapine treatment outcome and were compared at baseline and last observation. Results: All patients had normal baseline EEGs, and 10 patients (50%) later
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
showed EEG abnormalities. There were no significant differences between the EEG normal and EEG abnormal groups in mean age, gender, mean clozapine dose, or length of treatment with clozapine. Six patients (30%) experienced seizures; one with both tonic-clonic and myoclonic, one with tonic-clonic and four with myoclonic seizures. The mean baseline PANSS (T) scores were not significantly different between the EEG normal and EEG abnormal groups, but the mean score in the EEG abnormal group was significantly lower than that in the EEG normal group at the final follow-up. The response rate was not significantly different between the two groups. Discussion: The incidence of seizure in this study was higher than other reports in the literature. These results suggest that clozapine is more likely to cause seizures in the Japanese population. However, this study involved a small number of patients, so we cannot be certain that Japanese patients with schizophrenia have a higher risk of seizure with clozapine use; additional studies with larger samples are needed to verify our observation. All patients who experienced seizures in this study were successfully treated with valproate or lamotrigine without clozapine discontinuation. Cott (2007) described the treatment of clozapine-associated seizures with dosage reduction and/or the addition of an antiepileptic drug. It has been reported that clozapine-induced EEG abnormalities occur in a dose-dependent manner and correlated with serum level of clozapine. However, Centorrino et al. (2002) reported that clinical factors associated with EEG abnormalities included hypertension and age over 40 years old; they described no relationship between dose and EEG abnormalities. In this study, the mean dose of clozapine was no significantly different between the EEG abnormal and EEG normal groups. In half of the patients with EEG abnormalities, the clozapine dose was <300 mg. The relationship between clozapine dosage and EEG abnormality remains controversial. The baseline PANSS (T) was not significantly different between patients with normal and abnormal EEGs. However, the PANSS (T) from the last observation was significantly lower in the EEG abnormal group, indicating that EEG abnormalities appeared after clozapine treatments were associated with a good clinical response to clozapine.
Poster #M6 CARDIOMETABOLIC RISKS OF BLONANSERIN AND PEROSPIRONE IN THE MANAGEMENT OF SCHIZOPHRENIA: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS Taro Kishi 1,2 , Yuki Matsuda 3 , Nakao Iwata 1 1 Department of Psychiatry, Fujita Health University School of Medicine; 2 PhD; 3 Department of Psychiatry,Fujita Health University school of Medicine Background: The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia. Methods: We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics. Results: In total, 4 blonanserin studies (n=1080) were identified [vs. risperidone (2 studies, n=508); vs. haloperidol (2 studies, n=572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = −0.86, 95% confidence intervals = −1.36 to −0.36, p=0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA1c levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n=256), olanzapine (n=20), quetiapine (n=28), risperidone (n=53), aripiprazole (n=49), haloperidol (n=75), or mosapramine (n=81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels. Discussion: Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.
S191
Poster #M7 NEGATIVE SELF AND OTHER SCHEMAS AND INSECURE ATTACHMENT MEDIATE THE ASSOCIATION BETWEEN CHILDHOOD INTERPERSONAL ADVERSITY AND THE NONCLINICAL PSYCHOSIS PHENOTYPE Tamara Sheinbaum 1 , Thomas R. Kwapil 2 , Sergi Ballespí 3 , Neus Barrantes-Vidal 1,4 1 Department of Clinical and Health Psychology, Autonomous University of Barcelona; 2 Department of Psychology, University of North Carolina at Greensboro; 3 Universitat Autònoma de Barcelona; 4 Department of Mental Health, Health Foundation Sant Pere Claver (Barcelona) Background: There is mounting evidence indicating that interpersonal adversity in childhood is associated with psychotic phenomena in clinical and nonclinical populations. Among the psychological mechanisms that have been suggested to underlie this association, negative self and other schemas and insecure attachment styles have received increasing theoretical attention. However, there is scant empirical research investigating these predictions, particularly in regards to insecure attachment. The present study investigated the associations of childhood interpersonal trauma with nonclinical psychotic phenomena, and the role of negative self and other schemas and insecure attachment styles as potential mediators of the associations between early trauma exposure and nonclinical psychotic phenomena. Methods: At the initial assessment, 547 Spanish young adults completed a battery of self-report questionnaires, including measures of schizotypy, suspiciousness, psychotic-like experiences, traumatic childhood experiences, self and other schemas, and attachment style. At the second assessment, a subset of these participants (n=214), oversampled for high schizotypy and psychotic-like experiences, completed interview measures of prodromal symptoms, schizophrenia-spectrum personality disorders, childhood trauma, and attachment style. Results: At the initial assessment, physical/emotional trauma was significantly associated with positive and negative schizotypy, suspiciousness, and psychotic-like experiences. Results from the bootstrapping analyses indicated that negative self-schemas, negative other-schemas, and fearful attachment significantly mediated these associations. At the second assessment, physical/emotional trauma was significantly associated with positive and negative prodromal symptoms and schizophrenia-spectrum personality traits. Bootstrapping analyses indicated that insecure attachment was a significant mediator of these associations. Discussion: Childhood physical/emotional trauma was associated with the nonclinical psychosis phenotype across two time points and with both self-report and interview measures. These associations were mediated by theory-driven psychological mechanisms. Although the present study cannot determine causality, the findings are consistent with theoretical accounts suggesting that interpersonal childhood trauma may contribute to the formation of negative cognitive schemas and insecure attachment patterns, which, in turn, may impact upon the development and expression of the extended psychosis phenotype.
Poster #M8 POSITIVE ALLOSTERIC MODULATION OF MGLUR5 REVERSES THE AKT SIGNALING DEFICITS IN SERINE RACEMASE KNOCKOUT MICE, A GENETIC MODEL OF SCHIZOPHRENIA DUE TO NMDA RECEPTOR HYPOFUNCTION Darrick T. Balu 1,2 , Shunsuke Takagi 2 , Jose Bartolomé 3 , Thomas Steckler 3 , Carrie Jones 4 , P. Jeffrey Conn 4 , Joseph Coyle 2 1 Harvard Medical School; 2 McLean Hospital; 3 Janssen Research and Development; 4 Vanderbilt Center for Neuroscience Drug Discovery Background: There is substantial evidence that hypofunction of the Nmethyl-D-aspartate receptor (NMDAR) is a core pathophysiological mechanism underlying schizophrenia. We have previously demonstrated that serine racemase knockout (SR−/−) mice exhibit neuroanatomical and behavioral similarities to schizophrenia, as well as reductions in hippocampal Akt/glycogen synthase kinase 3 (GS3K)/mammalian target of rapamycin (mTOR) signaling that can be reversed with three weeks of D-serine treatment. Traditional metabotropic glutamate receptor 5 (mGluR5) positive allosteric modulators (PAMs) enhance NMDAR activity through circuits that are regulated by NMDARs and are currently being developed to ameliorate