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NOVEL ATYPICAL ANTIPSYCHOTIC AGENTS
Vijay Vinay,Singh Mahendra,Agrawal Mayank,Sharma Shailesh
International Research Journal of Pharmacy , 2011,
Abstract: Antipsychotics are a group of drugs commonly but not exclusively used to treat psychosis. Antipsychotic agents are grouped in two categories: Typical and Atypical antipsychotics. The first antipsychotic was chlorpromazine, which was developed as a surgical anesthetic. The first atypical anti-psychotic medication, clozapine, was discovered in the 1950s, and introduced in clinical practice in the 1970s. Both typical and atypical antipsychotics are effective in reducing positive and negative symptoms of schizophrenia. Blockade of D2 receptor in mesolimbic pathway is responsible for antipsychotic action. Typical antipsychotics are not particularly selective and also block Dopamine receptors in the mesocortical pathway, tuberoinfundibular pathway, and the nigrostriatal pathway. Blocking D2 receptors in these other pathways is thought to produce some of the unwanted side effects. Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, narcoleptic malignant syndrome, and hyperprolactinemia. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia (TD).
Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia  [PDF]
Tomiki Sumiyoshi,Takashi Uehara
Frontiers in Behavioral Neuroscience , 2013, DOI: 10.3389/fnbeh.2013.00140
Abstract: Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.
Cost-effectiveness of early responders versus early nonresponders to atypical antipsychotic therapy  [cached]
Peng X,Ascher-Svanum H,Faries DE,Stauffer VL
ClinicoEconomics and Outcomes Research , 2011,
Abstract: Xiaomei Peng1, Haya Ascher-Svanum1, Douglas E Faries1, Virginia L Stauffer1, Sara Kollack-Walker1, Bruce J Kinon1, John M Kane21Eli Lilly and Company, Indianapolis, Indiana; 2Zucker Hillside Hospital, Department of Psychiatry, Glen Oaks, New York, USABackground: To compare the cost-effectiveness of treating early responders versus early nonresponders to an atypical antipsychotic (risperidone) and the cost-effectiveness of treating early nonresponders maintained on risperidone versus those switched to olanzapine.Methods: This post hoc analysis used data from a randomized, double-blind, 12-week schizophrenia study (Study Code: HGMN, n = 628). Participants were initially assigned to risperidone therapy. Early response was defined as a ≥ 20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to two weeks. Early responders continued on risperidone, whereas early nonresponders were randomized in a double-blind manner to continue on risperidone or switch to olanzapine for 10 additional weeks. Early responders and early nonresponders maintained on risperidone were compared for health-state utilities (benefits) and total cost over the 12-week study; early nonresponders maintained on risperidone or switched to olanzapine were compared from randomization (10-week period). Utilities were derived from the PANSS and adverse events. Mixed models were used to assess group differences in utilities. Treatment costs were calculated based on health states. Incremental cost-effectiveness ratios were then utilized to compare treatment groups.Results: Early responders to risperidone had significantly greater total utility and lower total treatment costs than early nonresponders to risperidone. Compared with early nonresponders who continued on risperidone, those who were switched to olanzapine had significantly higher total utility scores at endpoint and numerically lower total treatment costs, reflecting significantly lower nonmedication treatment costs, even though medication costs were significantly higher compared with generic risperidone.Conclusion: Treatment of early responders was more cost-effective than treatment of early nonresponders to atypical antipsychotic therapy. Switching early nonresponders to olanzapine resulted in improved treatment effectiveness, met the criteria for some dominance, and appeared modestly more cost-effective than maintaining treatment with generic risperidone.Keywords: cost-benefit analysis, olanzapine, risperidone, treatment outcome, schizophrenia
Cost-effectiveness of early responders versus early nonresponders to atypical antipsychotic therapy
Peng X, Ascher-Svanum H, Faries DE, Stauffer VL, Kollack-Walker S, Kinon BJ, Kane JM
ClinicoEconomics and Outcomes Research , 2011, DOI: http://dx.doi.org/10.2147/CEOR.S16859
Abstract: st-effectiveness of early responders versus early nonresponders to atypical antipsychotic therapy Original Research (2804) Total Article Views Authors: Peng X, Ascher-Svanum H, Faries DE, Stauffer VL, Kollack-Walker S, Kinon BJ, Kane JM Published Date April 2011 Volume 2011:3 Pages 79 - 87 DOI: http://dx.doi.org/10.2147/CEOR.S16859 Xiaomei Peng1, Haya Ascher-Svanum1, Douglas E Faries1, Virginia L Stauffer1, Sara Kollack-Walker1, Bruce J Kinon1, John M Kane2 1Eli Lilly and Company, Indianapolis, Indiana; 2Zucker Hillside Hospital, Department of Psychiatry, Glen Oaks, New York, USA Background: To compare the cost-effectiveness of treating early responders versus early nonresponders to an atypical antipsychotic (risperidone) and the cost-effectiveness of treating early nonresponders maintained on risperidone versus those switched to olanzapine. Methods: This post hoc analysis used data from a randomized, double-blind, 12-week schizophrenia study (Study Code: HGMN, n = 628). Participants were initially assigned to risperidone therapy. Early response was defined as a ≥ 20% improvement on the Positive and Negative Syndrome Scale (PANSS) total score from baseline to two weeks. Early responders continued on risperidone, whereas early nonresponders were randomized in a double-blind manner to continue on risperidone or switch to olanzapine for 10 additional weeks. Early responders and early nonresponders maintained on risperidone were compared for health-state utilities (benefits) and total cost over the 12-week study; early nonresponders maintained on risperidone or switched to olanzapine were compared from randomization (10-week period). Utilities were derived from the PANSS and adverse events. Mixed models were used to assess group differences in utilities. Treatment costs were calculated based on health states. Incremental cost-effectiveness ratios were then utilized to compare treatment groups. Results: Early responders to risperidone had significantly greater total utility and lower total treatment costs than early nonresponders to risperidone. Compared with early nonresponders who continued on risperidone, those who were switched to olanzapine had significantly higher total utility scores at endpoint and numerically lower total treatment costs, reflecting significantly lower nonmedication treatment costs, even though medication costs were significantly higher compared with generic risperidone. Conclusion: Treatment of early responders was more cost-effective than treatment of early nonresponders to atypical antipsychotic therapy. Switching early nonresponders to olanzapine resulted in improved treatment effectiveness, met the criteria for some dominance, and appeared modestly more cost-effective than maintaining treatment with generic risperidone.
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
The effect of verbalization strategy on wisconsin card sorting test performance in schizophrenic patients receiving classical or atypical antipsychotics
Alessandro Rossi, Enrico Daneluzzo, Annarita Tomassini, Francesca Struglia, Roberto Cavallaro, Enrico Smeraldi, Paolo Stratta
BMC Psychiatry , 2006, DOI: 10.1186/1471-244x-6-3
Abstract: The aim of this paper is to evaluate different executive performance and response to verbalization, a strategy of the Wisconsin Card Sorting Test (WCST) remediation, in subjects on classical vs atypical antipsychotic (AP) treatment.Sixty-three schizophrenic subjects undertook the WCST under standard and modified (verbalization) administration. Subjects were stratified by the kind of WCST response (i.e. good, poor and remediable) and AP treatment (i.e. atypical vs. classical).Subjects on atypical APs showed a better performance than those on classical ones. More poor performers who did not remediate were seen in the sample with classical Aps while subjects who remediated the performance were seen in the subgroup with atypical APs only. An increase of perseverative and total errors was seen in poor performers subjects on classical APs.Subjects on atypicals showed a better cognitive pattern in terms of WCST performance. Since the naturalistic assignment of medication we cannot draw conclusions about its effect on cognitive performance and its interaction with cognitive remediation potential. However the data lead us to hypothesize that subjects with potential room for remediation did so with the atypical APs.Cognitive deficits are important targets for intervention in patients with schizophrenia to favor clinical and functional success. Executive skills are relevant for dealing with novel and complex situations, crucial for occupational outcome and independent living of people with schizophrenia [1,2]. Several studies reported that a large part of these people improve their executive performance by remediation strategies and cognitive therapies [3-5].A number of reports showed en encouraging remediation in some patients' executive deficits thanks to the use of 'information processing strategies'. This has been mostly investigated using Wisconsin Card Sorting Test (WCST), and verbalization has been found the most efficacious procedure to obtain the performance improveme
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-
Orbitofrontal lobe volume deficits in Antipsychotic-Naive schizophrenia: A 3-Tesla MRI study
Behere Rishikesh,Kalmady Sunil,Venkatasubramanian Ganesan,Gangadhar B
Indian Journal of Psychological Medicine , 2009,
Abstract: Background: Prefrontal cortex deficits have been consistently demonstrated in schizophrenia. The orbitofrontal lobe (OFL), a critical component of the prefrontal cortex, subserves social and neuro-cognitive functions. While these functional impairments are established in schizophrenia, the OFL volume deficits have not been well studied, especially in antipsychotic-naοve patients. Aim: To study OFL volume deficits in antipsychotic-naοve schizophrenia patients in comparison with matched healthy controls using high-resolution 3-tesla (3T) magnetic resonance imaging (MRI). Materials and Methods: Fourteen antipsychotic-naοve schizophrenia patients (DSM-IV) and 14 age-, sex-, handedness- and education-matched healthy controls were scanned using 3T MRI. Psychopathology was assessed in the patient group using the scale for assessment of negative symptoms and the scale for assessment of positive symptoms (SAPS). The OFL volume was measured using Region of Interest (ROI)-based manual morphometry technique, with good inter-rater reliability (intra-class correlation coefficient = 0.98). Results: Total OFL volume was significantly smaller in schizophrenia patients (43.3 ± 9.6 mL) in comparison with healthy controls (52.1 ± 12.2 mL) after controlling for the potential confounding effects of age, sex and intracranial volume (F = 5.3, P = .03). Duration of untreated psychosis did not correlate significantly with OFL volumes. There was a trend towards significant negative correlation between the left and total OFL volumes and SAPS scores (r = -0.49, P = .06). Conclusion: OFL volume deficits might underlie the pathogenesis of schizophrenia symptoms with possible neuro-developmental origins.
The Effects of Atypical Antipsychotic Usage Duration on Serum Adiponectin Levels and Other Metabolic Parameters  [cached]
Elif Oral,Mustafa Gulec,Nezahat Kurt,Sumeyra Yilmaz
Eurasian Journal of Medicine , 2011,
Abstract: Objective: Although atypical antipsychotics are well-tolerated and effective treatment options for schizophrenia, they have metabolic side effects, including weight gain and increased risk of Type II Diabetes Mellitus (DM). Adiponectin, produced exclusively in adipocytes, is the most abundant serum adipokine. Low levels of adiponectin are correlated with DM, insulin resistance and coronary heart disease. Usage of atypical antipsychotics may create a risk of metabolic syndrome. The aim of this study was to evaluate the effects of antipsychotic usage on parameters related to development of metabolic syndrome.Materials and Methods: A total of 27 patients (n=27) (13 women and 14 men) were recruited from our out-patient psychiatry clinic. All patients had been treated with atypical antipsychotics for at least 3 months and were in remission. Patients were evaluated for levels of HDL (High Density Lipoprotein), LDL (Low Density Lipoprotein ), TG (Triglyceride) total cholesterol and fasting blood glucose, body weight, BMI (Body Mass Index), waist circumference and serum adiponectin levels. Results: Serum adiponectin levels were significantly lower (p:0.000) and body weights were significantly higher (p:0.003) in the patients who had been using atypical antipsychotics for longer than a year in comparison to patients who had been using atypical antipsychotics for one year or less.Conclusion: Our findings supported the hypothesis that the length of administration of atypical antipsychotics has an effect on metabolic changes. They also highlight the fact that when investigating metabolic changes generated by atypical antipsychotic effects, the length of time that the patient has been on the atypical antipsychotics should also be considered.
Hematological Side Effects of Atypical Antipsychotic Drugs  [PDF]
Serap Erdogan
Psikiyatride Guncel Yaklasimlar , 2009,
Abstract: Atypical antipsychotics cause less frequently extrapyramidal system symptoms, neuroleptic malignant syndrome and hyperprolactinemia than typical antipsychotics. However hematological side effects such as leukopenia and neutropenia could occur during treatment with atypical antipsychotics. These side effects could lead to life threatening situations and the mortality rate due to drug related agranulocytosis is about 5-10%. There are several hypothesis describing the mechanisms underlying drug induced leukopenia and/or neutropenia such as direct toxic effects of these drugs upon the bone marrow or myeloid precursors, immunologic destruction of the granulocytes or supression of the granulopoiesis. Clozapine is the antipsychotic agent which has been most commonly associated with agranulocytosis. A nitrenium ion which is formed by the bioactivation of clozapine is thought to have an important role in the pathophysiogy of this adverse effect. Aside from clozapine, there are several case reports reporting an association between olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole and leukopenia. We did not find any study or case report presenting amisulpride or sulpride related hematological side effects in our literature search. Patients who had hematological side effects during their previous antipsychotic drug treatments and who had lower baseline blood leukocyte counts, have higher risk to develop leukopenia or neutropenia during their current antipsychotic treatment. Once leukopenia and neutropenia develops, drugs thought to be responsible for this side effect should be discontinued or dosages should be lowered. In some cases iniatition of lithium or G-CSF (granulocyte colony-stimulating factor) therapy may be helpful in normalizing blood cell counts. Clinicans should avoid any combination of drugs known to cause hematological side effects. Besides during antipsychotic treatment, infection symptoms such as fever, cough, sore throat or fatigue should be evaluated closely and routinely. In this review, all up to date studies including case reports presenting or searching for atypical antipsychotic drugs related hematological side effects have been reviewed and possible mechanisms leading to these adverse effects and suggested treatment modalities have been discussed.
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