ineligible patients were those with active suicidal state. Diagnosis of residual state schizophrenia, schizopreniform disorder or schizoaffective disorder. Breastfeeding women, pregnant or at risk of being pregnant. Patients that took any experimental medication within 30 days before baseline or had untreated or clinical significant rectal, endocrine, hepatic, respiratory, hematologic, immunologic, malignant or cardiovascular disease. Also patients with neurological illnesses or previously exposed to asenapine.
Treated population N=180. Intent-to-treat (ITT) N=174. Finished trial N=73.The percentage of patients that completed the trial was higher for Asenapine (46%) and Risperidone (42%) groups compared with placebo (34%) group. A high drop out rate for all groups (54% for Asenapine, 66% for placebo and 58% for risperidone)Incidence of withdrawal due to lack of efficacy was lower for asenapine. Incidence of withdrawal due to adverse effects was similar for asenapine (10% of treated patients, 19 withdrawals), placebo (11% and 17%) and risperidone (7% and 12%)
Table 3 shows no difference between treatments in the different scores.
A limitation to this study is the high incidence of discontinuance (59.3 % in average all groups). This might be due to a fixed dose and not a flexible dose, that permits adjustment based on clinical effects. This also reflects the high rates of discontinuance characteristics of drug trials in schizophrenic patients.
Asenapine In Schizophrenia
Efficacy and Tolerability of Asenapine in Acute Schizophrenia: A placebo and Risperidone-Controlled Trial Potkin, S., Cohen, M. Panagides, J.Dep. Psychiatry and Human Behavior, University of California, Irvine. Brain Imaging Center, Irvine
SummaryOBJECTIVE: To asses the efficacy, tolerability and safety of the investigationalpsychopharmacologic agent asenapine versus placebo in patients with acuteschizophreniaRATIONALE: There is not current adequate pharmacologic control for the fullrange of symptoms in schizophrenia.RESULTS: Asenapine treatment produced statistically significant greaterimprovement scores in positive and negative schizophrenic symptoms comparedwith placebo. Furthermore, it was well tolerated and was not associated withweight gain or prolactin elevation.
IntroductionAsenapine is a novel atypical psychopharmacologic agent in clinical development fortreatment for schizophrenia and bipolar disorder.Effectiveness of antipsychotic agents is measured against controlling positivesymptoms and prevention or delay in relapse. All psychopharmacologic agentameliorate positive symptoms to varying degree but not completely. There is not adequate or consistent control of negative symptomsAsenapine modulates activity at dopamine D2 receptors to control positivesymptoms of schizophrenia. Asenapine shows almost not affinity for muscarinicreceptors and have minimal risks of anticholinergic side effects.Atypical antipsychotics adverse effects include weight gain, diabetes, dyslipidemia,sexual dysfunction, sedation, and others.The unusual pharmacologic characteristics of asenapine may contribute to afavorable clinical profile in controlling schizophrenia with a high degree of safety andtolerability
MethodsTRIAL DESIGN: Treatment randomly assigned. Double blind, double-dummy, 3-arm, fixeddose, 6-week, placebo and risperidone-controlled. Institution’s ethics committee orreview board-approvedPATIENT ELIGIBILITY: ≥ 18 years old. Schizophrenia diagnosis within the disorganized,paranoid, catatonic or undifferentiated subtypesPRIMARY OUTCOME: Improvement from Baseline in Positive and Negative SyndromeScale (PANSS) SECONDARY OUTCOME: Changes in Clinical Global Impressions-Severity of Illness (CGI-S)TREATMENTS: Sublingual asenapine titrated from 1 mg b.i.d. day 1, increasing 1 mg b.i.dto reach 5 mg b.i.d at day 5 (plus oral placebo). Continued at 5 mg b.i.d.Oral risperidone titrated from 1mg b.i.d day 1, increasing 1 mg b.i.d to reach 3 mg b.i.dat day 3 (plus sublingual placebo). Continued at 3 mg b.i.d.Placebo group received oral and sublingual placebo b.i.d.
ResultsTable 1. Demographics and Baseline Clinical CharacteristicsCharacteristics Asenapine Placebo RisperidoneIntent-to-treat N 58 60 56Men, treated N (%) 46 (7) 49 (79) 36 (61)Mean age years (range) 38 (21-70) 42 (22-68) 43 (22-61)Ethnicity white N (%) 25 (42) 20 (32) 25 (42) black N (%) 28 (47) 32 (52) 26 (44)Paranoid diagnosis N (%) 50 (85) 60 (97) 50 (85)Present episode < 1month N (%) 34 (58) 39 (63) 44 (75)Present episode 1-6 months N (%) 21 (36) 16 (26) 11 (19)Episodic with prominentnegative symptoms N (%) 23 (39) 20 (32) 22 (37)Continuous episodic with Prominent negative symptoms N (%) 11 (19) 9 (15) 10 (17) Absent, other pattern, other 25 (42) 33 (53) 27 (46)Treated population N=180
Results Figure 1. Patient dispositiona Randomly assigned (N=182) Asenapine 5 mg bid N=60 Risperidone 3 mg bid N=60 Placebo bid N=62 DC before treatment N=1 DC before treatment N=1 N=60 Treated N=59 Treated N=62 Treated DC N=32 DC N=34 DC N=41 Lack of efficiency N=9 Lack of efficiency N=16 Lack of efficiency N=18 Adverse effects N=6 Adverse effects N=4 Adverse effects N=7 N=27 (46%) Other N=17 N=25 (42%) Other N=14 N=21 (34%) Other N=16 Completed Trial Completed Trial Completed TrialaNumber of patients randomly assigned, treated and with completed treatment, with reasons for discontinuation (DC) Figure 2. Primary measure of efficacy in the intent-to-treat population: change from baseline in PANSS total score a Week ✻p <.05 asenapine vs placebo LSM Change From Baseline ⁑p ≤ .005 asenapine vs placebo ℇ p = 0.001 asenapine vs placebo ✻ ℇ a The ℇ ⁑ ⁑ change from baseline in the total score on PANSS was determined at study end (6 weeks) or end of treatment with last observed Asenapine Risperidone Placebo data carried forward, using last square mean Baseline value 96.48 Baseline value 92.18 Baseline value 92.43 (LSM) and 2-factor analysis of variance
Results Figure 3. Secondary measure of efficacy in the intent-to-treat population a A. Changes from baseline CGI-S scores B. Changes from baseline PANSS positive symptom scores Week Week ✻p < .05 asenapine vs placebo LSM Change From Baseline LSM Change From Baseline ✝p ≤ .01 asenapine vs placebo ⁑p ≤ 0.005 asenapine vs placebo ‖p < 0.05 asenapine vs placebo ¶ p < 0.01 asenapine vs placebo ‖ # p < 0.005 asenapine vs placebo ‖ ‖ ‖ ¶ ‖ # ‖ ⁑ ⁑ ✝ ✝ ⁑ ✝ ✻ Asenapine Risperidone Placebo Asenapine Risperidone Placebo Baseline value 4.67 Baseline value 4.59 Baseline value 4.59 Baseline value 25.21 Baseline value 24.70 Baseline value 24.12C. Changes from baseline PANSS negative symptom scores D. Changes from baseline PANSS general psychopathology scores Week Week a The changes from baseline LSM Change From Baseline LSM Change From Baseline in scores on A, B, C, and D were determined at study end or end of treatment, using last square mean ✻ (LSM) and 2-factor analysis of variance ✝ ✝ ✻ ✻ ⁑ ⁑ ⁑ ✝ Asenapine Risperidone Placebo Asenapine Risperidone Placebo Baseline value 24.07 Baseline value 21.86 Baseline value 23.10 Baseline value 47.21 Baseline value 45.63 Baseline value 45.22
Results Table 2. Incidence of adverse events in ≥ 10% Table 3. Changec from baseline to end point of patients in any treatment group in mean scores on extrapyramidal symptomWHOa preferred Patients N (%)b rating instrumentsterm Asenapine Placebo Risperidone Asenapine Placebo RisperidoneInsomnia 11(19) 8 (13) 13(22) (N=56-57) (N=59-60) (N=56)Somnolence 11(19) 8 (13) 9 (15)Nausea 11 (19) 8 (13) 7 (12) RATING SCALE BL Change BL Change BL ChangeAnxiety 10 (17) 9 (15) 9 (15) BAS 1.00 -0.21 0.53 0.25 0.68 0.14Agitation 9 (15) 15 (24) 11 (19) SAS 1.11 -0.32 0.64 -0.24 0.75 0.05Headache 8 (14) 17 (27) 13 (22) AIMS 1.05 0.04 0.93 0.46 1.36 -0.02Vomiting 8 (14) 7 (11) 3 (5)Constipation 6 (10) 6 (10) 4 (7) C Negativechange indicates improvementPsychosis 6 (10) 4 (6) 4 (7) Abbreviations: BL= Baseline. BAS=Barnes Akathisia Scale.Dizziness 5 (8) 9 (15) 4 (7) SAS=Simpson-Angus Scale. AIMS=Abnormal involuntaryDyspepsia 4 (7) 5 (8) 7 (12) Movement ScaleUpper respiratoryTract infection 4 (7) 3 (5) 6 (10)Pain 3 (5) 4 (6) 6 (10)Fatigue 2 (3) 4 (6) 6 (10)Hypertonia 0 (0) 2 (3) 7 (12)a World Health organizationb Adverse effects not mutually exclusive between groups
ResultsFigure 4. Treatment effects on body weighta Figure 5. Treatment effects on serum prolactina (≥ 7% ) weight gain (% of patients) Incidence of clinically significant Mean change from baseline (μg/L) A Asenapine Risperidone Placebo (5 mg bid) (N=46) (3 mg bid) (N=47) (bid) (N=54) Week Asenapine Risperidone Placebo aProlactine levels assessed at weekly intervals B Mean weight gain (Kg) to study end (6 weeks) or end of treatment (last observation carried forward) Asenapine Risperidone Placebo a Effectson body weight were assessed at study end or at end of treatment in terms of (A) incidence of clinical significant weight gain (≥ 7% increase from baseline) and (B) actual mean weight gain
Conclusions1. Asenapine 5 mg b.i.d. was superior to placebo in treating the positiveand negative symptoms of schizophrenia.2. Ripseridone 3 mg b.i.d. was only superior to placebo in positivesymptoms score, not in negative symptoms.3. Incidence of clinically significant weight gain was similar for asenapineand placebo. Asenapine and placebo had similar effects onprolactinelevation. Risperidone had a higher incidence of weight gain andon levels of prolactincompared to placebo.4. Asenapine 5 mg b.i.d. was effective and well tolerated in the treatmentof acute schizophrenia and may be a useful option in patients withnegative symptoms.