F53. DOSE REDUCTION OF HIGH-DOSE FIRST-GENERATION ANTIPSYCHOTICS OR SWITCH TO ZIPRASIDONE IN LONG-STAY PATIENTS WITH SCHIZOPHRENIA: A 1-YEAR DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL

Abstract Background Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA). Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms or side effects. Methods In a randomized double-blind trial, we compared the effect of FGA dose reduction (to equivalent of 5 mg/day haloperidol) (n=24) or switching to ziprasidone 160 mg/day (n=24). Negative symptoms after 1 year of treatment were primary outcome measure. Treatment failure was defined as a prolonged (>4 weeks) or repeated relapse. Results Negative symptoms did not change significantly during dose reduction nor was there a significant difference between treatments. Neurological side effects diminished in both conditions. Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference in favour of FGA dose reduction. More patients in the ziprasidone condition (46%) than in the FGA condition (21%) relapsed. Although some recovered within 4 weeks, treatment failed in 25% of the patients in the ziprasidone condition and in 17% of the patients in the FGA condition (non-significant differences). In about 80% of patients, doses could be reduced without a prolonged increase in symptom severity. Discussion In long-stay patients with severe schizophrenia, reducing high doses of FGA to a dose equivalent of 5 mg/day haloperidol or switching to ziprasidone did not improve negative symptoms. Reducing antipsychotic doses was feasible in most patients, although the risk of relapse is substantial. Neither FGA dose reduction nor ziprasidone seems an adequate alternative to clozapine for treatment-resistant schizophrenia.


F51. INTEGRATED COGNITIVE REMEDIATION THERAPY PREVENTS RELAPSES IN SCHIZOPHRENIA OUTPATIENTS DURING 8-YEARS FOLLOW-UP
Daniel Mueller* ,1 , Conny Steichen 1 , Annina R. Reymond 1 , Volker Roder 1 1 University Hospital of Psychiatry and Psychotherapy, Bern Background: Relapse prevention is a major aim of any treatment for schizophrenia patients.In general, recent meta-analyses showed that one third of schizophrenia patients relapse in the first year after treatment, which corresponds with rehospitalization.Since years, study data support evidence for successful relapse prevention of psycho-educative and family therapy approaches in combination with pharmacological treatment.So far little is known about the impact of Cognitive Remediation Therapy (CRT) on relapse prevention.Methods: The purpose of this RCT was to investigate whether additional CRT could prevent relapses compared to treatment as usual (TAU) defined as pharmacological and other psychosocial treatments.The CRT approach of choice was the Integrated Neurocognitive Therapy (INT) developed in our lab.INT is a group approach consisting of 4 modules including interventions on all the neuro-and social cognitive domains, defined by the MATRICS initiative, as well as educational, emotion regulation and stress reduction tasks.In this international multicenter study, a total of 156 stabilized schizophrenia outpatients, diagnosed with DSM-IV, participated.From this sample, 71 participants of two out of eight centers could be observed during a follow-up of 1, 5 and 8 years, regarding number of relapses and days of rehospitalization.Relapses were defined as increased symptoms followed by rehospitalization.Results: One year after therapy, no marked differences between INT and TAU groups in relapse rates were evident.But during 5-and 8-year follow-up, 78% and 83% of TAU patients relapsed compared to 48% and 52% of INT patients suggesting a significant benefit of INT.TAU patients suffered from more than 2 relapses after 5 years and 2.5 relapses after 8 years.In comparison, INT patients showed 0.9 relapses after 5 and 1.4 relapses after 8 years.After the 5 years follow-up there was a highly significant difference between INT and TAU, and after the 8-years a statistical tendency favoring INT could be found.Regarding the days of hospitalization, TAU patients presented a mean value of 8 days during 1 year after treatment, 90 days after 5 years and 105 days after 8 years compared to INT patients with 1.2 days after 1 year, 19 days after 5 years and 35 days after 8 years.The comparison after 1 year was close to significant, the other ones were clearly significant favoring again the INT intervention.
Discussion: These data on INT intervention support evidence for an impact of CRT on relapse prevention in a 1, 5 and 8 years follow-up.However, the identification of mechanisms of change within INT treatment needs further research.
Background: Long-term efficacy and safety data from prospective studies in adolescents with schizophrenia are limited.Lurasidone is an atypical antipsychotic that has demonstrated efficacy in the treatment of schizophrenia in both adults and adolescents.The aim of the current open-label trial was to obtain long-term data on the safety and effectiveness of lurasidone in adolescents with schizophrenia.Methods: Patients ages 13-17 with schizophrenia were randomized to 6 weeks of double-blind (DB) treatment with lurasidone 40 mg/d, 80 mg/d or placebo.Patients who completed this study were eligible to enroll in a 2-year, openlabel (OL), flexible-dose (20-80 mg/d) extension study in which patients were continued on lurasidone, or switched from placebo to lurasidone.These data are the results of an interim analysis of the 2-year study.Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score (responder criteria, ≥20% reduction from double-blind baseline).
Results: A total of 271 patients completed 6 weeks of double-blind treatment and entered the 2-year extension study.At the time of the interim analysis, 132 patients had completed 52 weeks of treatment (24 patients were 2-year study completers; 96 patients were still ongoing; and 12 patients had discontinued after 52 weeks); 57 patients were still ongoing in the first 1-year of treatment; and 82 patients terminated prior to week 52 (28 patients due to withdrawal of consent; 23 due to adverse events; 9 due to lack of efficacy; and 22 for other reasons).Mean PANSS total score at double-blind baseline was 93.5.Overall mean change from double-blind to open-label baseline (after 6 weeks of treatment) was -17.5 (for patients assigned to lurasidone vs. placebo in the initial 6-week study, mean change was: -19.8 vs. -12.9).Overall mean change from double-blind baseline in the PANSS total score at weeks 28 (n=215), 52 (n=133), 76 (n=86), and 104 (n=24) was -29.2, -34.0, -35.0, and -34.1, respectively.Responder rates at week 52 and week 104 were 91.7% and 100%, respectively.During open-label treatment, the most common adverse events were headache (21.8%), nausea (11.8%), and anxiety (11.8%); 6.6% of patients reported an adverse event as severe.Median change in laboratory parameters from double-blind baseline to weeks 52 and 104, respectively, were: total cholesterol, -2.0 and -5.0 mg/dL; triglycerides, +3.5 and +3.0 mg/dL; hemoglobin A1c, 0.0 and 0.1%; prolactin in female, +0.5 and -0.5 ng/mL and males, +0.15 and +3.5 ng/mL; and mean change from DB baseline in weight at weeks 52 and 104 were 3.8 and 7.2 kg, vs. an expected weight gain of 3.3 and 5.1 kg, based on the gender-and-age specific CDC growth chart.Discussion: In adolescents with schizophrenia, long-term treatment with lurasidone was associated with continued improvement in symptoms of schizophrenia.After one year of lurasidone treatment, minimal effects were observed on body weight, lipids, and glycemic indices.Background: Long-stay patients with severe schizophrenia are frequently treated with high doses of first-generation antipsychotics (FGA).Dose reduction or switching to ziprasidone may reduce the severity of negative symptoms or side effects.Methods: In a randomized double-blind trial, we compared the effect of FGA dose reduction (to equivalent of 5 mg/day haloperidol) (n=24) or switching to ziprasidone 160 mg/day (n=24).Negative symptoms after 1 year of treatment were primary outcome measure.Treatment failure was defined as a prolonged (>4 weeks) or repeated relapse.Results: Negative symptoms did not change significantly during dose reduction nor was there a significant difference between treatments.Neurological side effects diminished in both conditions.Positive symptoms, excited symptoms, and emotional distress worsened over time with ziprasidone, resulting in a significant difference in favour of FGA dose reduction.More patients in the ziprasidone condition (46%) than in the FGA condition (21%) relapsed.Although some recovered within 4 weeks, treatment failed in 25% of the patients in the ziprasidone condition and in 17% of the patients in the FGA condition (non-significant differences).In about 80% of patients, doses could be reduced without a prolonged increase in symptom severity.Discussion: In long-stay patients with severe schizophrenia, reducing high doses of FGA to a dose equivalent of 5 mg/day haloperidol or switching to ziprasidone did not improve negative symptoms.Reducing antipsychotic doses was feasible in most patients, although the risk of relapse is substantial.Neither FGA dose reduction nor ziprasidone seems an adequate alternative to clozapine for treatment-resistant schizophrenia.

F54. PHARMACOLOGICAL ENHANCEMENT OF COGNITION AND SOCIAL COGNITION IN THE PSYCHOSIS SPECTRUM
M. Mercedes Perez-Rodriguez* ,1 , Daniel Rosell 1 , Scott Moeller 1 , Prantik Kundu 1 , Margaret McCLure 1 , Erin Hazlett 1 , Antonia New 1 1 Icahn School of Medicine at Mount Sinai Background: Abnormalities in cognition and social cognition represent a core feature of the schizophrenia spectrum disorders.Schizotypal personality disorder (SPD) is a milder disorder within the schizophrenia spectrum, characterized by attenuated, schizophrenia-like traits without overt psychosis.Study 1: Working memory impairments are a core cognitive deficit in schizophrenia and SPD.The dopamine D1 receptor is a promising target to enhance working memory.We aimed to test the effect of the D1 agonist dihydrexidine (DAR-0100A) to enhance working memory in patients with SPD.Study 2: Oxytocin modulates social cognition.However, oxytocin's effect on social cognitive errors in the schizophrenia spectrum remains unexplored.We aimed to: 1) characterize social cognitive (mentalizing) errors in SPD patients and test their relationship with positive and negative symptoms of psychosis; 2) test the effect of intranasal oxytocin on mentalizing errors.Methods: Study 1: We performed a randomized, double blind, placebocontrolled trial of DAR-0100A (15 mg/150 ml of normal saline i.v. over 30 min) in medication-free SPD patients (n=16).Study 2: Subjects: 15 SPD patients, 15 healthy controls [HC], and 15 psychiatric controls (PC).Intervention: intranasal oxytocin 24/40IU/placebo.Measures: Movie for the Assessment of Social Cognition (MASC), a naturalistic video task measuring mentalizing accuracy, "no mentalizing" errors, "hypomentalizing" errors and "hypermentalizing" errors.The "hyper-hypomentalizing ratio" can be computed to capture the predominant mentalizing tendency; PANSS; Schizotypal Personality Questionnaire, SPQ.Mentalizing measures were compared across groups (SPD, HC, PC), and treatments (oxytocin 24IU/40IU vs placebo) using ANOVA.Pearson correlations assessed the relationship between social cognition and symptoms.Results: Study 1: Treatment with dihydrexidine (DAR-0100A) was associated with significantly improved working memory performance relative to placebo, with a very large effect size (Cohen's d=1.14).Study 2: SPD patients had lower mentalizing accuracy (F=10.11;df=1;p=0.003),made more "No mentalizing" or "hypomentalizing" errors (F=12.92;df=1;p=0.001),and had lower hyper-hypomentalizing ratios than HCs (F=2.84;df=1;p=0.099,trendlevel).In a subset of patients -including 8 SPD-, a single dose of intranasal oxytocin significantly increased the hyper-hypomentalizing ratio (F=6.84,df=1,p=0.019)and increased visual attention to social cues."No mentalizing" and "hypomentalizing" errors were significantly correlated with negative symptoms."Hypermentalizing" errors were significantly correlated with positive symptoms and the "ideas of reference" and "suspiciousness" SPQ subscales.Discussion: Study 1: These preliminary findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments.Study 2: As hypothesized, SPD patients had impaired, less accurate social cognition, and made more "no mentalizing" and "hypomentalizing" errors, correlated with negative symptoms.Conversely, "hypermentalizing errors" were correlated with positive symptoms.Oxytocin increased the tendency to hypermentalize.This effect may normalize the abnormalities found at baseline in SPD patients.These results support the role of social cognitive impairments as an underlying factor of positive and negative symptoms of psychosis, with specific associations with paranoid and delusional traits.Our results also suggest that intranasal oxytocin modulates social cognitive errors in the psychosis spectrum.Background: Accumulating evidence indicates that cognitive remediation(CR) is effective for improving various cognitive deficits in adult patients with schizophrenia.Although reports of brain plasticity in older adults and the service needs of chronic mid-aged and older patients with schizophrenia are increasing, very few randomized controlled trials of CR have been conducted in mid-aged and older inpatients with schizophrenia.We investigated the efficacy of individualized CR on the cognitive impairments of mid-aged and older inpatients with schizophrenia within the context of comprehensive psychiatric rehabilitation(PR) by comparing the results obtained with PR only and treatment as usual(TAU).Methods: Fifty-seven mid-aged and older individuals with schizophrenia (age mean: 50.07 sd: 6.01) and mild to moderate cognitive deficits were enrolled.All participants stayed in long-stay closed ward hospital.Thirtyeight who were undergoing PR were randomly assigned to CR + PR (N = 19) or PR-only (N = 19) groups.For PR groups (CR+PR group and PR only group) received comprehensive inpatient PR, including optimal

F53.
DOSE REDUCTION OF HIGH-DOSE FIRST-GENERATION ANTIPSYCHOTICS OR SWITCH TO ZIPRASIDONE IN LONG-STAY PATIENTS WITH SCHIZOPHRENIA: A 1-YEAR DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL Poster Session II 1 MHO Rivierduinen; 2 MHO North Holland North; 3 Bureau Beta; 4 Academic Medical Center, University of Amsterdam