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P.3.c.017 The effect of second generation antipsychotics on cognition in patients with early psychosis
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P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical)
P.3.c.016 Olanzapine in the treatment of catatonic stupor − two case reports and discussion K. Todorova1 ° 1 University Hospital “St. Marina”, III psychiatric department, Varna, Bulgaria Purpose of the study: First described by Kahlbaum in 1874 the concept of catatonia still remains among the enigmatic phenomena in psychiatry. Most would agree that it is a non-specific but strongly differenciated syndrome which may appear in different psychiatric (schizophrenia, affective disorders) or general medical conditions (infections, endocrinologic, neurological, metabolic) or as an adverse event of a treatment. As a catatonic manifestation, catatonic stupor is one of the dramatic psychiatric presentations which is becoming relatively rare nowadays and usually necessitates intensive care unit treatment. Evidence suggests that classical antipsychotics may aggravate catatonia, but novel antipsychotics might be useful, relieving the underlying psychopathology and having beneficial effects on different brain functions [1]. Successful olanzapine treatment of catatonia has been reported in some case reports in literature [2,3]. The aim of this paper is to present two cases of successive treatment of catatonic stupor with olanzapine and to discuss the available recently published data on the matter. Methods: A review of the literature from the last decade on the use of olanzapine in the treatment of catatonia and two case reports. Summary of results: The reviewed literature consists of case reports and retrospective studies and considers mainly patients with schizophrenia. We present case reports of non schizophrenic patients with catatonic stupor resolved after treatment with olanzapine. One of our patients was with ICD-10 diagnosis of Bipolar Disorder (DSM-IV − Bipolar II Disorder) − severe depressive episode with psychotic features, the other with ICD-10 − Organic catatonic disorder (DSM-IV − Catatonic disorder due to influenza) with no previous psychiatric history. Physical and neurological examinations and paraclinical investigatons showed no abnormalities. Both patients were antipsychotic-na¨ıve. Olanzapine was administered in its intramascular formulation after 24 hours of uneffective treatment with i.m.diazepam. Olanzapine initiation was followed by a quick reduction of the catatonic symptoms and final resolution of the condition in both patients. Intramuscular olanzapine was replaced by peroral formulation, which remained as a part of the long term therapy of the Bipolar patient, and was stopped with the discharge of the other one. The exact pathophysiology of catatonia has not yet been revealed. Several hypothesis regarding neurotransmitter dysfunction have been forwarded. Although dopamine is a major neurotransmitter in the frontal circuits, they are also modified by GABA and serotonergic projections from the dorsal raphe nucleus. Cortical dysfunction and dysregulation in cortical-subcortical circuits between motor/premotor cortex and basal ganglia and GABA cortical disfunction possibly account for the catatonic symptoms. Olanzapine as an atypical antipsychotic has the ability of concomitant blockage of 5-HT2A and D2 receptors with relative stimulation of the mesocortical dopamine pathway with respect to the nigrostriatal and mesolimbic pathways thus having beneficial effects on different brain functions including underlying psychopathology. Yet it is difficult to speculate by which mechanism it might relieve non malignant catatonia.
Conclusion: There is no evidence from clinical trials whether atypical antipsychotics prove to be a therapeutic option in catatonia. Their use besides or replacing benzodiazepines or electroconvulsive therapy should be considered as an alternative option with caution until controlled trials provide further data. References [1] Van der Eede, F., Van Hecke, J., Van Dalfsen, A., Van den Bossche, B., Cosyns, P., Sabbe, B.G.C., 2005 The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry 20, 422–429. [2] Babington, P.W., Spiegel, D.R., 2007 Treatment of catatonia with olanzapine and amantadine. Psychosomatics. 48, 534–536. [3] Gusman, C.S., Myung V.H.M., Wang Y.P., 2007 Treatment of periodic catatonia with olanzapine: a case report. Bras Psiquiatr 29, 380−5.
P.3.c.017 The effect of second generation antipsychotics on cognition in patients with early psychosis I. Montalvo1 ° , M. Creus1 , A. Guti´errez-Zotes1 , L. Ortega1 , R. Monseny1 , T. Feliu1 , J. Franch1 , J. Labad1 1 Hospital Psiqui`atric Universitari Institut Pere Mata IISPV Universitat Rovira, Early Intervention Service, Reus, Spain Introduction: Impairments in cognition are a core feature of schizophrenia and are already present at the time of the first psychotic episode. There is evidence supporting that specific impairments in cognitive performance are related to low functional outcomes [1]. Antipsychotic medications have been shown to be effective in improving psychotic symptomatology. However, the effect of pharmacologic treatment on cognition is still uncertain [2]. The purpose of the present study was to compare the effect of different second generation antipsychotics on the cognitive performance in patients with a first episode of psychosis. Methods: We included 50 subjects (40% female patients; main age 23.8 [standard deviation = 4.8]) with early psychosis, attending the Early Psychosis Program from Reus (Tarragona, Spain). The target population of our Program includes subjects between 18 and 35 years old with a first psychotic episode, with a psychotic disorder in the first five years of illness (defined as critical period) or at risk for psychosis (ultra-high-risk). A structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry, SCAN) was used to obtain a clinical diagnosis. Severity of psychotic symptoms was assessed with the PANSS. The MATRICS Consensus Cognitive Battery (MCCB) [3] was administered to evaluate cognitive function in all patients. This battery includes ten neuropsychological tests to assess seven cognitive domains commonly examined in studies of schizophrenia (Speed of Processing, Attention/Vigilance, Working Memory, Verbal learning, Visual Learning, Reasoning and Problem Solving and social Cognition) and the Overall Composite Score. Current antipsychotic treatment was requested. Of all participants, 17 (34%) were receiving risperidone, 8 (16%) paliperidone, 7 (14%) aripiprazole, 10 (20%) olanzapine. Statistical analyses were performed with SPSS v.17.0. We conducted a multiple linear regression analyses to explore the relationship between antipsychotic treatment and neurocognitive domains. For each cognitive domain, the T-scores (corrected for age and gender) were considered the dependent variable. Antipsychotic drugs were included in the equation as four independent variables (risperidone, paliperidone, aripiprazole and olanzapine). All these variables were included in each model with the enter
P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical) procedure. Standardized beta coefficients are shown in the results section. Results: The mean (standard deviation) PANSS scores of the sample were: PANSS-P = 10.6 (3.9); PANSS-N = 14.8 (6.7); PANSS-G = 31.6 (8.6). There were no significant differences in PANSS scores between treatments. Of all cognitive domains, antipsychotic treatment was not associated with speed of processing, attention/vigilance, working memory, reasoning and problem-solving, social cognition. Risperidone treatment was associated with a poorer cognitive performance in verbal learning (B = −0.305, p = 0.033) and visual learning (B = −0.286, p = 0.044). Aripiprazole was negatively associated with verbal learning (B = −0.395, p = 0.008) and visual learning (B = −0.355, p = 0.016). In the overall composite score, aripiprazole (B = −0.339, p = 0.031) was associated with a poorer cognitive performance. Conclusions: Our results, that might be considered preliminary due to the small sample size, suggest that risperidone and aripiprazole may have a worse cognitive profile compared to paliperidone and olanzapine in subjects with early psychosis. Of all cognitive domains, visual and verbal learning seem to be more clearly affected by antipsychotic treatment. References [1] Fett AK, Viechtbauer W, Dominguez MD, et al. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci. Biobehav. Rev. 35 (3), 573–588. [2] Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects. Schizophrenia Research 2007; 89: 211–224. [3] Rodriguez-Jimenez R, Bagney A, Garcia-Navarro C, et al. The MATRICS consensus cognitive battery (MCCB): Co-norming and standardization in Spain. Schizophrenia Research. 2012; 134(2−3): 279−84. Disclosure statement: This work was supported by grants from Fundaci´o La Marat´o de TV3 (092230/0922431) and from Instituto de Salud Carlos III (FIS, PI10/01607). Javier Labad has received an Intensification of Research Activity grant (Programme I3SNS-INT 11/323) from the Instituto de Salud Carlos III (Spain) during 2012
P.3.c.018 A placebo-controlled study of efficacy/ safety of aripiprazole intramuscular depot for long-term maintenance treatment of schizophrenia R. Sanchez1 ° , P. Perry1 , N. Jin1 , B. Johnson1 , R.A. Forbes1 , R.D. McQuade1 , W.H. Carson1 , W. Fleischhacker2 , J.M. Kane3 1 Otsuka Pharmaceutical Development and Commercialization, Global Clinical Development, Princeton, USA; 2 Medical University Innsbruck, Department of Psychiatry and Psychotherapy, Innsbruck, Austria; 3 The Zucker Hillside Hospital, The Hofstra North Shore-LIJ School of Medicine, Glen Oaks, USA Purpose: To evaluate the efficacy, safety and tolerability of a oncemonthly aripiprazole intramuscular depot (ARI-IM-depot) for the maintenance treatment of schizophrenia in adults. Methods: Subjects 18−60 years old requiring chronic treatment with an antipsychotic were eligible. Subjects not already on aripiprazole monotherapy were cross-titrated from other antipsychotic(s) to oral aripiprazole monotherapy during the 4−6week oral conversion phase (Phase 1). All subjects entered a 4−12-week oral stabilization phase (Phase 2) and received oral
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aripiprazole (10−30 mg/day). Subjects meeting stability criteria for 4 weeks then entered an intramuscular depot stabilization phase (Phase 3), wherein they received ARI-IM-depot injections every 4 weeks (400 mg, single decrease to 300 mg permitted) with coadministration of oral aripiprazole tablets for the first 2 weeks. Subjects meeting stability criteria for 12 consecutive weeks were randomized (2:1) to ARI-IM-depot or placebo during a 52-week, double-blind maintenance phase (Phase 4). The primary endpoint was time to impending relapse. Safety and tolerability were also assessed. Summary: 710 subjects entered the oral stabilization phase, 576 progressed to ARI-IM-depot stabilization and 403 subjects were randomized to double-blind, placebo-controlled treatment. The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis (conducted after 64 relapses or 50% of total events). Time-to-impending relapse was significantly delayed in ARI-IM-depot compared with placebo in both interim and final analyses (p < 0.0001, log-rank test). The rate of impending relapse was significantly lower with ARI-IM-depot than placebo at endpoint (final analysis: 10.0%, n = 27/269 vs. 39.6%, n = 53/134; hazard ratio [HR], 5.0; 95% confidence interval [CI], 3.15–8.02, p < 0.0001). Improvements in PANSS Total score were maintained with ARI-IM-depot treatment but showed significant worsening with placebo (mean change in PANSS at Week 52: ARI-IM-depot = 1.4, placebo = 11.6, p < 0.0001). All-cause discontinuation in Phase 4, other than study termination by sponsor, was significantly lower with ARI-IM-depot compared with placebo (p < 0.0001); discontinuation rates were 24.9% vs 54.5%, respectively. Discontinuations due to treatmentemergent adverse events (TEAEs) were: Phase 1, 3.8% (24/632); Phase 2, 3.0% (21/709); Phase 3, 4.9% (28/576); and Phase 4, 7.1% (19/269). Most AEs were mild or moderate; severe AEs were rare (<5.0% incidence in all phases). TEAEs 5% in Phases 3 and 4 were insomnia, headache, anxiety, akathisia, and weight increase, with injection-site pain reported at >5% only in Phase 3 and tremor the only AE 5% and at least twice the rate of placebo in Phase 4. The incidence of treatment-emergent extrapyramidal symptoms (EPS) and EPS-related events was similar in Phases 3 and 4: ARI-IM-depot 14.9% vs. placebo 9.7%. Mean baseline weight in Phases 3 and 4 was 81.2–84.8 kg. Mean changes in weight from baseline were: Phase 3, −0.2 kg; Phase 4, ARI-IMdepot vs. placebo, −0.2 vs. −0.4 kg. There were no unusual shifts in laboratory values or fasting metabolic parameters in Phases 3 and 4, including similar low rates between ARI-IM-depot and placebo in the double-blind phase. Conclusions: ARI-IM-depot significantly delayed time to impending relapse compared with placebo and was well tolerated as maintenance treatment in schizophrenia. Disclosure statement: Raymond Sanchez, Pamela Perry, Na Jin, Brian Johnson, Robert A. Forbes, Robert D. McQuade, and William H. Carson are employees of Otsuka Pharmaceutical Development and Commercialization, Inc. Wolfgang Fleischhacker has received research grants from Otsuka, Pfizer, Janssen, Alkermes, and Eli Lilly as well as consulting honoraria from Lundbeck, Roche, BMS, Otsuka, Janssen, Pfizer, Unitedbiosource, MedAvante, Sunovion and Merck. He has received speaker honoraria from Lundbeck, Sunovion, Janssen, Eli Lilly, Otsuka and AstraZeneca, and holds stock from MedAvante. John M. Kane has received honoraria for lectures and/or consulting from Alkermes, Amgen, BMS, Cephalon, Esai, Boehringer Ingelheim, Eli Lilly, Intracellular Therapeutics, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Pierre Fabre, Proteus, Roche, Sunovion and Targacept. He is a shareholder of MedAvante.
P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical)
P.3.c.016 Olanzapine in the treatment of catatonic stupor − two case reports and discussion K. Todorova1 ° 1 University Hospital “St. Marina”, III psychiatric department, Varna, Bulgaria Purpose of the study: First described by Kahlbaum in 1874 the concept of catatonia still remains among the enigmatic phenomena in psychiatry. Most would agree that it is a non-specific but strongly differenciated syndrome which may appear in different psychiatric (schizophrenia, affective disorders) or general medical conditions (infections, endocrinologic, neurological, metabolic) or as an adverse event of a treatment. As a catatonic manifestation, catatonic stupor is one of the dramatic psychiatric presentations which is becoming relatively rare nowadays and usually necessitates intensive care unit treatment. Evidence suggests that classical antipsychotics may aggravate catatonia, but novel antipsychotics might be useful, relieving the underlying psychopathology and having beneficial effects on different brain functions [1]. Successful olanzapine treatment of catatonia has been reported in some case reports in literature [2,3]. The aim of this paper is to present two cases of successive treatment of catatonic stupor with olanzapine and to discuss the available recently published data on the matter. Methods: A review of the literature from the last decade on the use of olanzapine in the treatment of catatonia and two case reports. Summary of results: The reviewed literature consists of case reports and retrospective studies and considers mainly patients with schizophrenia. We present case reports of non schizophrenic patients with catatonic stupor resolved after treatment with olanzapine. One of our patients was with ICD-10 diagnosis of Bipolar Disorder (DSM-IV − Bipolar II Disorder) − severe depressive episode with psychotic features, the other with ICD-10 − Organic catatonic disorder (DSM-IV − Catatonic disorder due to influenza) with no previous psychiatric history. Physical and neurological examinations and paraclinical investigatons showed no abnormalities. Both patients were antipsychotic-na¨ıve. Olanzapine was administered in its intramascular formulation after 24 hours of uneffective treatment with i.m.diazepam. Olanzapine initiation was followed by a quick reduction of the catatonic symptoms and final resolution of the condition in both patients. Intramuscular olanzapine was replaced by peroral formulation, which remained as a part of the long term therapy of the Bipolar patient, and was stopped with the discharge of the other one. The exact pathophysiology of catatonia has not yet been revealed. Several hypothesis regarding neurotransmitter dysfunction have been forwarded. Although dopamine is a major neurotransmitter in the frontal circuits, they are also modified by GABA and serotonergic projections from the dorsal raphe nucleus. Cortical dysfunction and dysregulation in cortical-subcortical circuits between motor/premotor cortex and basal ganglia and GABA cortical disfunction possibly account for the catatonic symptoms. Olanzapine as an atypical antipsychotic has the ability of concomitant blockage of 5-HT2A and D2 receptors with relative stimulation of the mesocortical dopamine pathway with respect to the nigrostriatal and mesolimbic pathways thus having beneficial effects on different brain functions including underlying psychopathology. Yet it is difficult to speculate by which mechanism it might relieve non malignant catatonia.
Conclusion: There is no evidence from clinical trials whether atypical antipsychotics prove to be a therapeutic option in catatonia. Their use besides or replacing benzodiazepines or electroconvulsive therapy should be considered as an alternative option with caution until controlled trials provide further data. References [1] Van der Eede, F., Van Hecke, J., Van Dalfsen, A., Van den Bossche, B., Cosyns, P., Sabbe, B.G.C., 2005 The use of atypical antipsychotics in the treatment of catatonia. Eur Psychiatry 20, 422–429. [2] Babington, P.W., Spiegel, D.R., 2007 Treatment of catatonia with olanzapine and amantadine. Psychosomatics. 48, 534–536. [3] Gusman, C.S., Myung V.H.M., Wang Y.P., 2007 Treatment of periodic catatonia with olanzapine: a case report. Bras Psiquiatr 29, 380−5.
P.3.c.017 The effect of second generation antipsychotics on cognition in patients with early psychosis I. Montalvo1 ° , M. Creus1 , A. Guti´errez-Zotes1 , L. Ortega1 , R. Monseny1 , T. Feliu1 , J. Franch1 , J. Labad1 1 Hospital Psiqui`atric Universitari Institut Pere Mata IISPV Universitat Rovira, Early Intervention Service, Reus, Spain Introduction: Impairments in cognition are a core feature of schizophrenia and are already present at the time of the first psychotic episode. There is evidence supporting that specific impairments in cognitive performance are related to low functional outcomes [1]. Antipsychotic medications have been shown to be effective in improving psychotic symptomatology. However, the effect of pharmacologic treatment on cognition is still uncertain [2]. The purpose of the present study was to compare the effect of different second generation antipsychotics on the cognitive performance in patients with a first episode of psychosis. Methods: We included 50 subjects (40% female patients; main age 23.8 [standard deviation = 4.8]) with early psychosis, attending the Early Psychosis Program from Reus (Tarragona, Spain). The target population of our Program includes subjects between 18 and 35 years old with a first psychotic episode, with a psychotic disorder in the first five years of illness (defined as critical period) or at risk for psychosis (ultra-high-risk). A structured clinical interview (Schedules for Clinical Assessment in Neuropsychiatry, SCAN) was used to obtain a clinical diagnosis. Severity of psychotic symptoms was assessed with the PANSS. The MATRICS Consensus Cognitive Battery (MCCB) [3] was administered to evaluate cognitive function in all patients. This battery includes ten neuropsychological tests to assess seven cognitive domains commonly examined in studies of schizophrenia (Speed of Processing, Attention/Vigilance, Working Memory, Verbal learning, Visual Learning, Reasoning and Problem Solving and social Cognition) and the Overall Composite Score. Current antipsychotic treatment was requested. Of all participants, 17 (34%) were receiving risperidone, 8 (16%) paliperidone, 7 (14%) aripiprazole, 10 (20%) olanzapine. Statistical analyses were performed with SPSS v.17.0. We conducted a multiple linear regression analyses to explore the relationship between antipsychotic treatment and neurocognitive domains. For each cognitive domain, the T-scores (corrected for age and gender) were considered the dependent variable. Antipsychotic drugs were included in the equation as four independent variables (risperidone, paliperidone, aripiprazole and olanzapine). All these variables were included in each model with the enter
P.3.c. Psychotic disorders and antipsychotics − Antipsychotics (clinical) procedure. Standardized beta coefficients are shown in the results section. Results: The mean (standard deviation) PANSS scores of the sample were: PANSS-P = 10.6 (3.9); PANSS-N = 14.8 (6.7); PANSS-G = 31.6 (8.6). There were no significant differences in PANSS scores between treatments. Of all cognitive domains, antipsychotic treatment was not associated with speed of processing, attention/vigilance, working memory, reasoning and problem-solving, social cognition. Risperidone treatment was associated with a poorer cognitive performance in verbal learning (B = −0.305, p = 0.033) and visual learning (B = −0.286, p = 0.044). Aripiprazole was negatively associated with verbal learning (B = −0.395, p = 0.008) and visual learning (B = −0.355, p = 0.016). In the overall composite score, aripiprazole (B = −0.339, p = 0.031) was associated with a poorer cognitive performance. Conclusions: Our results, that might be considered preliminary due to the small sample size, suggest that risperidone and aripiprazole may have a worse cognitive profile compared to paliperidone and olanzapine in subjects with early psychosis. Of all cognitive domains, visual and verbal learning seem to be more clearly affected by antipsychotic treatment. References [1] Fett AK, Viechtbauer W, Dominguez MD, et al. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: a meta-analysis. Neurosci. Biobehav. Rev. 35 (3), 573–588. [2] Woodward ND, Purdon SE, Meltzer HY, Zald DH. A meta-analysis of cognitive change with haloperidol in clinical trials of atypical antipsychotics: dose effects and comparison to practice effects. Schizophrenia Research 2007; 89: 211–224. [3] Rodriguez-Jimenez R, Bagney A, Garcia-Navarro C, et al. The MATRICS consensus cognitive battery (MCCB): Co-norming and standardization in Spain. Schizophrenia Research. 2012; 134(2−3): 279−84. Disclosure statement: This work was supported by grants from Fundaci´o La Marat´o de TV3 (092230/0922431) and from Instituto de Salud Carlos III (FIS, PI10/01607). Javier Labad has received an Intensification of Research Activity grant (Programme I3SNS-INT 11/323) from the Instituto de Salud Carlos III (Spain) during 2012
P.3.c.018 A placebo-controlled study of efficacy/ safety of aripiprazole intramuscular depot for long-term maintenance treatment of schizophrenia R. Sanchez1 ° , P. Perry1 , N. Jin1 , B. Johnson1 , R.A. Forbes1 , R.D. McQuade1 , W.H. Carson1 , W. Fleischhacker2 , J.M. Kane3 1 Otsuka Pharmaceutical Development and Commercialization, Global Clinical Development, Princeton, USA; 2 Medical University Innsbruck, Department of Psychiatry and Psychotherapy, Innsbruck, Austria; 3 The Zucker Hillside Hospital, The Hofstra North Shore-LIJ School of Medicine, Glen Oaks, USA Purpose: To evaluate the efficacy, safety and tolerability of a oncemonthly aripiprazole intramuscular depot (ARI-IM-depot) for the maintenance treatment of schizophrenia in adults. Methods: Subjects 18−60 years old requiring chronic treatment with an antipsychotic were eligible. Subjects not already on aripiprazole monotherapy were cross-titrated from other antipsychotic(s) to oral aripiprazole monotherapy during the 4−6week oral conversion phase (Phase 1). All subjects entered a 4−12-week oral stabilization phase (Phase 2) and received oral
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aripiprazole (10−30 mg/day). Subjects meeting stability criteria for 4 weeks then entered an intramuscular depot stabilization phase (Phase 3), wherein they received ARI-IM-depot injections every 4 weeks (400 mg, single decrease to 300 mg permitted) with coadministration of oral aripiprazole tablets for the first 2 weeks. Subjects meeting stability criteria for 12 consecutive weeks were randomized (2:1) to ARI-IM-depot or placebo during a 52-week, double-blind maintenance phase (Phase 4). The primary endpoint was time to impending relapse. Safety and tolerability were also assessed. Summary: 710 subjects entered the oral stabilization phase, 576 progressed to ARI-IM-depot stabilization and 403 subjects were randomized to double-blind, placebo-controlled treatment. The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis (conducted after 64 relapses or 50% of total events). Time-to-impending relapse was significantly delayed in ARI-IM-depot compared with placebo in both interim and final analyses (p < 0.0001, log-rank test). The rate of impending relapse was significantly lower with ARI-IM-depot than placebo at endpoint (final analysis: 10.0%, n = 27/269 vs. 39.6%, n = 53/134; hazard ratio [HR], 5.0; 95% confidence interval [CI], 3.15–8.02, p < 0.0001). Improvements in PANSS Total score were maintained with ARI-IM-depot treatment but showed significant worsening with placebo (mean change in PANSS at Week 52: ARI-IM-depot = 1.4, placebo = 11.6, p < 0.0001). All-cause discontinuation in Phase 4, other than study termination by sponsor, was significantly lower with ARI-IM-depot compared with placebo (p < 0.0001); discontinuation rates were 24.9% vs 54.5%, respectively. Discontinuations due to treatmentemergent adverse events (TEAEs) were: Phase 1, 3.8% (24/632); Phase 2, 3.0% (21/709); Phase 3, 4.9% (28/576); and Phase 4, 7.1% (19/269). Most AEs were mild or moderate; severe AEs were rare (<5.0% incidence in all phases). TEAEs 5% in Phases 3 and 4 were insomnia, headache, anxiety, akathisia, and weight increase, with injection-site pain reported at >5% only in Phase 3 and tremor the only AE 5% and at least twice the rate of placebo in Phase 4. The incidence of treatment-emergent extrapyramidal symptoms (EPS) and EPS-related events was similar in Phases 3 and 4: ARI-IM-depot 14.9% vs. placebo 9.7%. Mean baseline weight in Phases 3 and 4 was 81.2–84.8 kg. Mean changes in weight from baseline were: Phase 3, −0.2 kg; Phase 4, ARI-IMdepot vs. placebo, −0.2 vs. −0.4 kg. There were no unusual shifts in laboratory values or fasting metabolic parameters in Phases 3 and 4, including similar low rates between ARI-IM-depot and placebo in the double-blind phase. Conclusions: ARI-IM-depot significantly delayed time to impending relapse compared with placebo and was well tolerated as maintenance treatment in schizophrenia. Disclosure statement: Raymond Sanchez, Pamela Perry, Na Jin, Brian Johnson, Robert A. Forbes, Robert D. McQuade, and William H. Carson are employees of Otsuka Pharmaceutical Development and Commercialization, Inc. Wolfgang Fleischhacker has received research grants from Otsuka, Pfizer, Janssen, Alkermes, and Eli Lilly as well as consulting honoraria from Lundbeck, Roche, BMS, Otsuka, Janssen, Pfizer, Unitedbiosource, MedAvante, Sunovion and Merck. He has received speaker honoraria from Lundbeck, Sunovion, Janssen, Eli Lilly, Otsuka and AstraZeneca, and holds stock from MedAvante. John M. Kane has received honoraria for lectures and/or consulting from Alkermes, Amgen, BMS, Cephalon, Esai, Boehringer Ingelheim, Eli Lilly, Intracellular Therapeutics, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Pierre Fabre, Proteus, Roche, Sunovion and Targacept. He is a shareholder of MedAvante.