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New atypical antipsychotics for schizophrenia: iloperidone
Silvio Caccia, Luca Pasina, Alessandro Nobili
Drug Design, Development and Therapy , 2010, DOI: http://dx.doi.org/10.2147/DDDT.S6443
Abstract: typical antipsychotics for schizophrenia: iloperidone Review (8499) Total Article Views Authors: Silvio Caccia, Luca Pasina, Alessandro Nobili Published Date February 2010 Volume 2010:4 Pages 33 - 48 DOI: http://dx.doi.org/10.2147/DDDT.S6443 Silvio Caccia,1 Luca Pasina,2 Alessandro Nobili2 1Laboratory of Drug Metabolism, “Mario Negri” Institute for Pharmacological Research, Milan, Italy; 2Laboratory of Quality, Assessment of Geriatric Therapies and Services, “Mario Negri” Institute for Pharmacological Research, Milan, Italy Abstract: The optimal treatment of schizophrenia poses a challenge to develop more effective treatments and safer drugs, to overcome poor compliance, discontinuation and frequent switching with available antipsychotics. Iloperidone is a new dopamine type 2/serotonin type 2A (D2/5-HT2A) antagonist structurally related to risperidone, expected to give better efficacy with less extrapyramidal symptoms than D2 receptor antagonist antipsychotics. In double-blind phase III trials iloperidone reduced the symptoms of schizophrenia at oral doses from 12 to 24 mg. It was more effective than placebo in reducing positive and negative syndrome total score and Brief Psychiatric Rating scale scores; it was as effective as haloperidol and risperidone in post-hoc analysis. Its long-term efficacy was equivalent to that of haloperidol. The most common adverse events were dizziness, dry mouth, dyspepsia and somnolence, with few extrapyramidal symptoms and metabolic changes in short- and long-term studies in adults. Akathisia was rare, but prolongation of the corrected QT (QTc) interval was comparable to haloperidol and ziprasidone, which is of particular concern. Further comparative studies are needed to clarify the benefit/risk profile of iloperidone and its role in the treatment of schizophrenia.
New atypical antipsychotics for schizophrenia: iloperidone  [cached]
Silvio Caccia,Luca Pasina,Alessandro Nobili
Drug Design, Development and Therapy , 2010,
Abstract: Silvio Caccia,1 Luca Pasina,2 Alessandro Nobili21Laboratory of Drug Metabolism, “Mario Negri” Institute for Pharmacological Research, Milan, Italy; 2Laboratory of Quality, Assessment of Geriatric Therapies and Services, “Mario Negri” Institute for Pharmacological Research, Milan, ItalyAbstract: The optimal treatment of schizophrenia poses a challenge to develop more effective treatments and safer drugs, to overcome poor compliance, discontinuation and frequent switching with available antipsychotics. Iloperidone is a new dopamine type 2/serotonin type 2A (D2/5-HT2A) antagonist structurally related to risperidone, expected to give better efficacy with less extrapyramidal symptoms than D2 receptor antagonist antipsychotics. In double-blind phase III trials iloperidone reduced the symptoms of schizophrenia at oral doses from 12 to 24 mg. It was more effective than placebo in reducing positive and negative syndrome total score and Brief Psychiatric Rating scale scores; it was as effective as haloperidol and risperidone in post-hoc analysis. Its long-term efficacy was equivalent to that of haloperidol. The most common adverse events were dizziness, dry mouth, dyspepsia and somnolence, with few extrapyramidal symptoms and metabolic changes in short- and long-term studies in adults. Akathisia was rare, but prolongation of the corrected QT (QTc) interval was comparable to haloperidol and ziprasidone, which is of particular concern. Further comparative studies are needed to clarify the benefit/risk profile of iloperidone and its role in the treatment of schizophrenia.Keywords: iloperidone, pharmacology, pharmacokinetics, efficacy, safety
Effects of typical and atypical antipsychotic drugs on gene expression profiles in the liver of schizophrenia subjects
Kwang H Choi, Brandon W Higgs, Serge Weis, Jonathan Song, Ida C Llenos, Jeannette R Dulay, Robert H Yolken, Maree J Webster
BMC Psychiatry , 2009, DOI: 10.1186/1471-244x-9-57
Abstract: We performed genome-wide expression profiling to study effects of typical antipsychotics and atypical antipsychotics in the postmortem liver of schizophrenia patients using microarrays (Affymetrix U133 plus2.0). We classified the subjects into typical antipsychotics (n = 24) or atypical antipsychotics (n = 26) based on their medication history, and compared gene expression profiles with unaffected controls (n = 34). We further analyzed individual antipsychotic effects on gene expression by sub-classifying the subjects into four major antipsychotic groups including haloperidol, phenothiazines, olanzapine and risperidone.Typical antipsychotics affected genes associated with nuclear protein, stress responses and phosphorylation, whereas atypical antipsychotics affected genes associated with golgi/endoplasmic reticulum and cytoplasm transport. Comparison between typical antipsychotics and atypical antipsychotics further identified genes associated with lipid metabolism and mitochondrial function. Analyses on individual antipsychotics revealed a set of genes (151 transcripts, FDR adjusted p < 0.05) that are differentially regulated by four antipsychotics, particularly by phenothiazines, in the liver of schizophrenia patients.Typical antipsychotics and atypical antipsychotics affect different genes and biological function in the liver. Typical antipsychotic phenothiazines exert robust effects on gene expression in the liver that may lead to liver toxicity. The genes found in the current study may benefit antipsychotic drug development with better therapeutic and side effect profiles.Differential therapeutic and side effects of typical antipsychotic (AP) and atypical AP drugs in schizophrenia have been documented [1,2]. Typical APs such as haloperidol and phenothiazines induce elevation of serum prolactin, extrapyramidal symptoms and tardive dyskinesia, whereas atypical APs such as clozapine and olanzapine induce metabolic syndromes and elevation of liver enzyme levels [3-
Association of Typical versus Atypical Antipsychotics with Symptoms and Quality of Life in Schizophrenia  [PDF]
Koichiro Fujimaki, Terumichi Takahashi, Shigeru Morinobu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037087
Abstract: Background Several reports on patients with chronic schizophrenia suggest that atypical versus typical antipsychotics are expected to lead to better quality of life (QOL) and cognitive function. Our aim was to examine the association of chronic treatment with typical or atypical antipsychotics with cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms in long-hospitalized patients with schizophrenia. Methodology and Principal Findings The Hasegawa Dementia Scale-Revised (HDS-R), Brief Psychiatric Rating Scale (BPRS), the Schizophrenia Quality of Life Scale, translated into Japanese (JSQLS), and the Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) were used to evaluate cognitive function, psychiatric symptoms, QOL, and drug-induced extrapyramidal symptoms. We examined the correlation between the dose of antipsychotics and each measure derived from these psychometric tests. The student t-test was used to compare scores obtained from psychometric tests between patients receiving typical and atypical antipsychotics. Results showed significant correlations between chlorpromazine (CPZ)-equivalent doses of typical antipsychotics and atypical antipsychotics, and the total BPRS score and BPRS subscale scores for positive symptoms. CPZ-equivalent doses of typical antipsychotics were correlated with the JSQLS subscale score for dysfunction of psycho-social activity and DIEPSS score. Furthermore, the total BPRS scores, BPRS subscale score for positive symptoms, the JSQLS subscale score for dysfunction of psycho-social activity, and the DIEPSS score were significantly higher in patients receiving typical antipsychotics than atypical antipsychotics. Conclusion and Significance These findings suggest that long-term administration of typical antipsychotics has an unfavorable association with feelings of difficulties mixing in social situations in patients with chronic schizophrenia.
Structural effects of atypical antipsychotics: Implications for the meaning of cortical volume deficit in schizophrenia
Molina,Vicente;
The European Journal of Psychiatry , 2005, DOI: 10.4321/S0213-61632005000400004
Abstract: patients with schizophrenia have a smaller volume of cortex than healthy controls. nevertheless, the substrate of such deficit is not well understood a progressive loss of cortical gm in schizophrenia seemed supported by early studies with magnetic resonance imaging (mri) in which patients received typical drugs between the baseline and final scans. however, recent mri results challenge this notion and suggest that structural changes may depend, at least in part, on the type of treatment received. these data may be relevant for a correct interpretation of the substrate of cortical volume deficit in schizophrenia. if that deficit can be even reversed by treatment, as suggested by recent studies, a neuronal substrate seems unlikely. several lines of evidence instead support that glia cells may have a role in cortical structural and functional deficits in schizophrenia, which would be also in agreement with recent longitudinal results with mri in patients treated with atypical antipsychotics. these evidences are reviewed in this paper.
Structural effects of atypical antipsychotics: Implications for the meaning of cortical volume deficit in schizophrenia  [cached]
Vicente Molina
The European Journal of Psychiatry , 2005,
Abstract: Patients with schizophrenia have a smaller volume of cortex than healthy controls. Nevertheless, the substrate of such deficit is not well understood A progressive loss of cortical GM in schizophrenia seemed supported by early studies with magnetic resonance imaging (MRI) in which patients received typical drugs between the baseline and final scans. However, recent MRI results challenge this notion and suggest that structural changes may depend, at least in part, on the type of treatment received. These data may be relevant for a correct interpretation of the substrate of cortical volume deficit in schizophrenia. If that deficit can be even reversed by treatment, as suggested by recent studies, a neuronal substrate seems unlikely. Several lines of evidence instead support that glia cells may have a role in cortical structural and functional deficits in schizophrenia, which would be also in agreement with recent longitudinal results with MRI in patients treated with atypical antipsychotics. These evidences are reviewed in this paper.
Adherence and persistence to typical and atypical antipsychotics in the naturalistic treatment of patients with schizophrenia
Haya Ascher-Svanum, Baojin Zhu, Douglas E Faries, Jonathan P Lacro, Christian R Dolder, Xiaomei Peng
Patient Preference and Adherence , 2008, DOI: http://dx.doi.org/10.2147/PPA.S2940
Abstract: dherence and persistence to typical and atypical antipsychotics in the naturalistic treatment of patients with schizophrenia Original Research (5209) Total Article Views Authors: Haya Ascher-Svanum, Baojin Zhu, Douglas E Faries, Jonathan P Lacro, Christian R Dolder, Xiaomei Peng Published Date March 2008 Volume 2008:2 Pages 67 - 77 DOI: http://dx.doi.org/10.2147/PPA.S2940 Haya Ascher-Svanum1, Baojin Zhu1, Douglas E Faries1, Jonathan P Lacro2, Christian R Dolder3, Xiaomei Peng1 1Eli Lilly and Company, Outcomes Research, Indianapolis, IN, USA; 2VA San Diego Health Care System and Department of Psychiatry, University of California, San Diego, CA, USA; 3Wingate University School of Pharmacy, Wingate, NC, USA Objective: To compare adherence and persistence to typical versus atypical antipsychotics and between specific atypical agents in the usual care of schizophrenia and to examine the association between adherence and persistence. Method: Data were drawn from a 3-year prospective, nonrandomized, noninterventional study of schizophrenia conducted during 1997–2003. Initiators on haloperidol, risperidone, olanzapine, quetiapine, and clozapine with at least 1 year of follow-up were included (n = 878). Adherence (Medication Possession Ratio, MPR) and persistence (time to all-cause medication discontinuation) were assessed using medical record prescription information. Analyses employed multivariate statistics adjusted for group differences. Results: Overall, 58% of the patients were deemed adherent (MPR >80%). Adherence rates were higher: for atypical (59.4%) than typical antipsychotics (34.5%, p < 0.001), for clozapine (77%) than each comparator excluding olanzapine (p < 0.01), and for olanzapine (64%) than risperidone (57%, p = 0.027) and quetiapine (52%, p = 0.019). Differences between risperidone and quetiapine were not statistically significant. Adherence and persistence were highly correlated (r = 0.957, p < 0.001). Conclusion: In the usual care of schizophrenia, medication adherence and persistence appear to be highly correlated and to significantly differ between typical and atypical antipsychotics and among atypical agents. The choice of antipsychotic may play a meaningful role in patients’ adherence to and persistence with antipsychotic medications.
Time to discontinuation of atypical versus typical antipsychotics in the naturalistic treatment of schizophrenia
Haya Ascher-Svanum, Baojin Zhu, Douglas Faries, Ron Landbloom, Marvin Swartz, Jeff Swanson
BMC Psychiatry , 2006, DOI: 10.1186/1471-244x-6-8
Abstract: We used data from a large, 3-year, observational, non-randomized, multisite study of schizophrenia, conducted in the U.S. between 7/1997 and 9/2003. Patients who were initiated on oral atypical antipsychotics (clozapine, olanzapine, risperidone, quetiapine, or ziprasidone) or oral typical antipsychotics (low, medium, or high potency) were compared on time to all-cause medication discontinuation for 1 year following initiation. Treatment group comparisons were based on treatment episodes using 3 statistical approaches (Kaplan-Meier survival analysis, Cox Proportional Hazards regression model, and propensity score-adjusted bootstrap resampling methods). To further assess the robustness of the findings, sensitivity analyses were performed, including the use of (a) only 1 medication episode for each patient, the one with which the patient was treated first, and (b) all medication episodes, including those simultaneously initiated on more than 1 antipsychotic.Mean time to all-cause medication discontinuation was longer on atypical (N = 1132, 256.3 days) compared to typical antipsychotics (N = 534, 197.2 days; p < .01), and longer on atypicals compared to typicals of high potency (N = 320, 187.5 days; p < .01), medium potency (N = 140, 213.5 days; p < .01), and low potency (N = 74, 208.7 days; p < .01). Among the atypicals, only clozapine, olanzapine, and risperidone had significantly longer time to all-cause medication discontinuation compared to typicals, regardless of potency level, and compared to haloperidol with prophylactic anticholinergic treatment. When compared to perphenazine, a medium-potency typical antipsychotic, only clozapine and olanzapine had a consistently and significantly longer time to all-cause medication discontinuation. Results were confirmed by sensitivity analyses.In the usual care of schizophrenia patients, time to medication discontinuation for any cause appears significantly longer for atypical than typical antipsychotics regardless of the ty
Effectiveness and Tolerability (with focus on metabolic effects) of three atypical Antipsychotics in the treatment of schizophrenia- A 48 week observational study.
B B Surti,V J Patel,A P Chauhan,D M Bhatt
NHL Journal of Medical Sciences , 2013,
Abstract: Background and Objectives: The use of atypical antipsychotics in schizophrenia has increased. This prospective, observational study with was carried out with objectives of evaluation of effectiveness and tolerability with focus on metabolic side effects of atypical antipsychotics in schizophrenic outpatients over 48-weeks period.Materials and Methods: Outpatients of 18-65 years age, male or female, diagnosed with schizophrenia meeting DSM-IV diagnosis criteria of the disease, who were on risperidone or olanzapine or clozapine were included. Patients were observed at scheduled visits for subjective-wellbeing, global functioning, efficacy and illness severity/improvement, body weight and BMI, fasting biochemical parameters (blood glucose and lipid profile) and adverse effects over a period of 48 weeks.Results: Of 154 patients available post-baseline visit onwards, with respect to changes in subjective well-being, global functioning, PANSS total and CGI Improvement scores show three drug groups to have comparative improvement at endpoint over 48 weeks irrespective of baseline psychopathological scores. The clinically significant (≥ 7%) weight gain at endpoint (increase from baseline) was observed in 42 (27.3%) patients. However, no significant difference was found between three drug groups in this respect (p > 0.05). With respect to biochemical parameters, in case of fasting blood glucose, although borderline changes (100 to 125 mg/dL) were observed, no clinically significant changes (≥ 126 mg/dL) were observed. With respect to fasting lipid changes (total cholesterol, LDL cholesterol, triglycerides), there were 42 cases at week 12 (Ris 23, Ola 17, Cloz 2) of which 8 patients showed clinically significant lipid changes with overall female preponderance. Remaining 34 cases were with borderline lipid changes. Of 41 cases with lipid changes observed at endpoint, all had borderline changes. Tolerability profile of three drugs in safety group (N=168) found weight gain 53(31.5%) as most common adverse effect (AE) followed by extrapyramidal side effects in 26(15.5 %). Discontinuation due to all-cause (or any cause) was, Cloz: 0, Ola 12(19.3%), and Ris 18(20.6%) patients over a period of 48 weeks. The mean survival time (time-to-medication discontinuation till 48 weeks) was found 48.00 ± 00.00 weeks in clozapine group followed by risperidone 41.79±13.34 weeks and olanzapine 40.71±15.30 weeks. No significant difference was found between three groups (p > 0.05) with respect to discontinuation rate and time-to-all-cause discontinuation.Conclusion: Results of this pro
Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics
Douglas Faries, Haya Ascher-Svanum, Baojin Zhu, Christoph Correll, John Kane
BMC Psychiatry , 2005, DOI: 10.1186/1471-244x-5-26
Abstract: Data were drawn from a large prospective naturalistic study of patients treated for schizophrenia-spectrum disorders, conducted 7/1997–9/2003. Analyses focused on patients (N = 796) who were initiated during the study on olanzapine (N = 405), quetiapine (N = 115), or risperidone (N = 276). The percentage of patients with monotherapy on the index antipsychotic over the 1-year post initiation, and the cumulative number of days on monotherapy were calculated for all patients and for each of the 3 atypical antipsychotic treatment groups. Analyses employed repeated measures generalized linear models and non-parametric bootstrap re-sampling, controlling for patient characteristics.During the 1-year period, only a third (35.7%) of the patients were treated predominately with monotherapy (>300 days). Most patients (57.7%) had at least one prolonged period of antipsychotic polypharmacy (>60 consecutive days). Patients averaged 195.5 days on monotherapy, 155.7 days on polypharmacy, and 13.9 days without antipsychotic therapy. Olanzapine-initiated patients were significantly more likely to be on monotherapy with the initiating antipsychotic during the 1-year post initiation compared to risperidone (p = .043) or quetiapine (p = .002). The number of monotherapy days was significantly greater for olanzapine than quetiapine (p < .001), but not for olanzapine versus risperidone, or for risperidone versus quetiapine-initiated patients.Despite guidelines recommending the use of polypharmacy only as a last resort, the use of antipsychotic polypharmacy for prolonged periods is very common during the treatment of schizophrenia patients in usual care settings. In addition, in this non-randomized naturalistic observational study, the most commonly used atypical antipsychotics significantly differed on the rate and duration of antipsychotic monotherapy. Reasons for and the impact of the predominant use of polypharmacy will require further study.Guidelines for treating patients with schizop
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