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      Pharmacologic treatment of schizophrenia Translated title: Tratamiento farmacológico de la esquizofrenia Translated title: Traitement pharmacologique de la schizophrénie

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          Abstract

          Despite pharmacologic advances, the treatment of schizophrenia remains a challenge, and suboptimal outcomes are still all too frequent. Although treatment goals of response, remission, and recovery have been defined more uniformly, a good “effectiveness” measure mapping onto functional outcomes is still lacking. Moreover, the field has to advance in transferring measurement-based approaches from research to clinical practice. There is an ongoing debate whether, and which, first- or second-generation antipsychotics should be used. However, an individualized treatment approach needs to consider current symptoms, comorbid conditions, past therapeutic response, and adverse effects, as well as patient choice and expectations. Moreover, acute and long-term goals and effects of medication treatment need to be balanced. While the acute response to appropriately dosed first-generation antipsychotics may not differ much from second-generation antipsychotics, advantages of lower rates of extrapyramidal side effects, tardive dyskinesia, and, possibly, relapse may favor second-generation antipsychotics. However, when considering individual adverse effect prof iles, the differentiation into first- and second-generation antipsychotics as unified classes can not be upheld, and a more differentiated view and treatment selection is required. To date, clozapine is the only evidence-based treatment for refractory patients, and the role of antipsychotic polypharmacy and other augmentation strategies remains unclear, at best. To improve the treatment outcomes in schizophrenia, research efforts are needed that elucidate biomarkers of the illness and of treatment response (both therapeutic and adverse effects). Moreover, new treatment options are needed that affect nondopaminergic targets with relevance for symptom reduction, relapse prevention, enhanced efficacy for nonresponders, and reduced key adverse effects.

          Translated abstract

          A pesar de los progresos farmacológicos, el tratamiento de la esquizofrenia todavía constituye un desafío y los resultados insatisfactorios aun son bastante frecuentes. Aunque se han definido más uniformemente los objetivos terapéuticos de respuesta, remisión y récupération, aun falta una buena medición de “efectividad” para delimitar los resultados funcionales. Además, en esta área se tiene que avanzar en la transferencia de enfoques basados en mediciones que vayan desde la investigatión hasta la práctica clínica. Actualmente existe un debate orientado a si deben o no utilizarse antipsicóticos y cuáles de ellos, sean de primera o segunda generación. Sin embargo, un enfoque terapéutico individualizado requière tener en cuenta los síntomas actuales, las condiciones comórbidas, la respuesta terapéutica previa y los efectos adversos, como también la election del patente y sus expectativas. Por otra parte, se deben balancear los objetivos a corto y largo plazo, y los efectos del tratamiento medicamentoso. Aunque la respuesta aguda a dosis apropiadas de antipsicóticos de primera generacíon puede que no difiera mucho de los antipsicóticos de segunda generacíon, las ventajas de menores frecuencias de efectos secundarios extrapiramidales, disquinesia tardfa e incluso recaídas pueden darle ventaja a los antipsicóticos de segunda generation. Sin embargo, cuando se consideran los perfiles de efectos adversos individuales, puede que no sea suficiente la diferenciación entre antipsicóticos de primera y segunda generation como grupos de fármacos, y se requiera de un criterio más diferenciado y de una selection del tratamiento. A la fecha, la clozapina es el único tratamiento basado en la evidencia para los patentes refractarios, y aun no está del todo claro el papel de la polifarmacia antipsicótica y de otras estrategias potenciadoras. Para mejorar los resultados de los tratamientos en la esquizofrenia, se requière de esfuerzos que procedan de la investigation y que permitan identificar biomarcadores de la enfermedad y de la respuesta terapéutica (tanto los efectos deseables como los adversos). Además, se necesitan nuevas opciones terapéuticas que no estén dirigidas hacia los sistemas dopaminérgicos y que influyan en la reduction de los síntomas, la prevention de las recaídas, el aumento de la eficacia en los no respondedores y la reduction de los principales efectos adversos.

          Translated abstract

          Malgré des avancées pharmacologiques, la schizophrénie reste difficile à traiter et des résultats insatisfaisants sont encore trop fréquents. Les cibles thérapeutiques de réponse, rémission et rétablissement ont été définies de façon plus uniforme mais il manque encore une mesure convenable « d'efficacité » basée sur les capacités fonctionnelles des patients. De plus, dans ce domaine, il faut avancer en transférant les approches basées sur les mesures de la recherche à la pratique clinique. Savoir si il faut utiliser des antipsychotiques de 1 re ou de 2 e génération et lesquels, fait toujours l'objet de discussions. Un traitement personnalisé nécessite néanmoins d'envisager les symptômes actuels, la comorbidité, les réponses thérapeutiques antérieures, les effets indésirables ainsi que les choix et les attentes du patient. Il faut en outre mettre en balance les objectifs et les effets des traitements à court et à long termes. Alors qu'une réponse aiguë à des antipsychotiques de 1 re génération correctement dosés peut ne pas différer beaucoup d'une réponse à des antipsychotiques de 2 e génération, les bénéfices d'une fréquence moindre d'effets extrapyramidaux, de dyskinésie tardive et, peut-être, de rechute, font pencher la balance du côté des antipsychotiques de 2 e génération. Cependant, si l'on considère les profils individuels des effets secondaires, la distinction dans les antipsychotiques de 1 re et 2 e générations en tant que classes unifiées, ne tient pas et il est nécessaire d'avoir une vision plus différenciée et une sélection thérapeutique plus fine. À ce jour, la clozapine est le seul traitement ayant apporté ses preuves pour les patients résistants, le rôle d'une polythérapeutique antipsychotique et des autres stratégies d'augmentation restant au mieux obscur. L'amélioration des résultats du traitement dans la schizophrénie passe par des efforts de la recherche pour trouver des biomarqueurs de la maladie et de la réponse au traitement (effets thérapeutiques et effets indésirables). Ajoutons que de nouveaux choix de traitement sont nécessaires en ce qui concerne des cibles non dopaminergiques en tenant compte de la diminution des symptômes, de la prévention des rechutes, de l'augmentation de l'efficacité chez les non-répondeurs et de la diminution des effets indésirables majeurs.

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          Most cited references78

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          The positive and negative syndrome scale (PANSS) for schizophrenia.

          The variable results of positive-negative research with schizophrenics underscore the importance of well-characterized, standardized measurement techniques. We report on the development and initial standardization of the Positive and Negative Syndrome Scale (PANSS) for typological and dimensional assessment. Based on two established psychiatric rating systems, the 30-item PANSS was conceived as an operationalized, drug-sensitive instrument that provides balanced representation of positive and negative symptoms and gauges their relationship to one another and to global psychopathology. It thus constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness. Study of 101 schizophrenics found the four scales to be normally distributed and supported their reliability and stability. Positive and negative scores were inversely correlated once their common association with general psychopathology was extracted, suggesting that they represent mutually exclusive constructs. Review of five studies involving the PANSS provided evidence of its criterion-related validity with antecedent, genealogical, and concurrent measures, its predictive validity, its drug sensitivity, and its utility for both typological and dimensional assessment.
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            Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial.

            Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.
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              Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1).

              Second-generation (atypical) antipsychotics (SGAs) are more expensive than first-generation (typical) antipsychotics (FGAs) but are perceived to be more effective, with fewer adverse effects, and preferable to patients. Most evidence comes from short-term efficacy trials of symptoms. To test the hypothesis that in people with schizophrenia requiring a change in treatment, SGAs other than clozapine are associated with improved quality of life across 1 year compared with FGAs. A noncommercially funded, pragmatic, multisite, randomized controlled trial of antipsychotic drug classes, with blind assessments at 12, 26, and 56 weeks using intention-to-treat analysis. Fourteen community psychiatric services in the English National Health Service. Two hundred twenty-seven people aged 18 to 65 years with DSM-IV schizophrenia and related disorders assessed for medication review because of inadequate response or adverse effects. Randomized prescription of either FGAs or SGAs (other than clozapine), with the choice of individual drug made by the managing psychiatrist. Quality of Life Scale scores, symptoms, adverse effects, participant satisfaction, and costs of care. The primary hypothesis of significant improvement in Quality of Life Scale scores during the year after commencement of SGAs vs FGAs was excluded. Participants in the FGA arm showed a trend toward greater improvements in Quality of Life Scale and symptom scores. Participants reported no clear preference for either drug group; costs were similar. In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using FGAs rather than nonclozapine SGAs. Neither inadequate power nor patterns of drug discontinuation accounted for the result.
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                Author and article information

                Contributors
                The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY and Albert Einstein College of Medicine, Bronx, NY, USA
                The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY and Albert Einstein College of Medicine, Bronx, NY, USA
                Journal
                Dialogues Clin Neurosci
                Dialogues Clin Neurosci
                Dialogues in Clinical Neuroscience
                Les Laboratoires Servier (France )
                1294-8322
                1958-5969
                September 2010
                : 12
                : 3
                : 345-357
                Affiliations
                The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY and Albert Einstein College of Medicine, Bronx, NY, USA
                The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY and Albert Einstein College of Medicine, Bronx, NY, USA
                Author notes
                Article
                10.31887/DCNS.2010.12.3/jkane
                3085113
                20954430
                4e95f3e8-ae54-476a-8edb-9646bc570f6f
                Copyright: © 2010 LLS

                This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by-nc-nd/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Pharmacological Aspects

                Neurosciences
                outcome,second-generation antipsychotic,first-generation antipsychotic,pharmacology,schizophrenia

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