INTRODUÇÃO: Considera-se a clozapina como padrão-ouro para o tratamento de pacientes com esquizofrenia refratária, com base principalmente em sua eficácia comprovadamente superior em relação aos antipsicóticos típicos. No entanto, os dados acerca do uso de outros antipsicóticos atípicos ainda são escassos ou divergentes. Tendo em vista que o uso de clozapina está associado a várias limitações, existe uma necessidade não atendida de alternativas terapêuticas eficazes e seguras para a esquizofrenia refratária. MÉTODOS: Foi realizada uma revisão sistemática de estudos controlados e randomizados (ECRs), comparando clozapina aos outros antipsicóticos atípicos, em pacientes com esquizofrenia refratária. Foram realizadas metanálises avaliando a eficácia das intervenções, medida por meio de escalas de avaliação de sintomas psicóticos. A resposta ao tratamento foi medida por meio da porcentagem de respondedores ou pela mudança média ou valores finais dos escores das escalas. Quando possível, foram realizadas metanálises da comparação entre clozapina e outro antipsicótico atípico específico. Os tamanhos de efeito foram dados pelo risco relativo (RR) ou pela diferença entre médias (DM), ponderada ou padronizada, acompanhados dos respectivos intervalos de confiança de 95%. As metanálises foram realizadas utilizando-se o modelo de efeitos fixos, ou aleatórios, no caso de haver heterogeneidade entre os estudos. Foram realizadas análises de sensibilidade, excluindo-se estudos que haviam incluído pacientes intolerantes junto à população refratária. RESULTADOS: Onze ECRs foram incluídos, representando 1182 pacientes, com 12 comparações entre clozapina e antipsicóticos atípicos: quatro com risperidona, um com ziprasidona e sete com olanzapina. Considerados como um grupo, não foi possível determinar diferenças no tamanho de efeito entre a clozapina e os outros antipsicóticos atípicos em nenhum tipo de medida geral de sintomas psicóticos. A metanálise que combinou as mudanças médias e os valores finais da PANSS e da BPRS apresentou uma diferença de médias de 0,00 (IC95%= -0,12, 011). Foi observada superioridade marginal dos antipsicóticos atípicos para sintomas negativos, medidos pelos valores finais da PANSS (DM= -1,96, IC95%= -3,44, -0,48). Foi observado que os estudos que compararam a clozapina à olanzapina tiveram doses finais médias altas de olanzapina (médias de 17,2 mg/d a 33,6 mg/d), o que pode ter influenciado nos resultados.CONCLUSÕES: Os antipsicóticos atípicos, particularmente a olanzapina em doses altas, podem representar uma alternativa de tratamento para pacientes com esquizofrenia refratária / BACKGROUND: Clozapine is considered as the gold standard for the treatment of patients with refractory schizophrenia, based upon its well established superior efficacy against typical antipsychotics. Nevertheless, data on other atypical antipsychotics are still scarce or divergent for this population. Considering that clozapine use is associated to several caveats, there is an unmet need for safe and efficacious alternative therapeutic approaches for refractory schizophrenia. METHODS: It was conducted a systematic review of randomized clinical trials (RCTs) comparing clozapine to other atypical antipsychotics in patients with refractory schizophrenia. Metanalyses assessing the efficacy of interventions were performed. Efficacy was measured by psychotic symptoms scales. Response to treatment was measured by the percentage of responders or by mean change or endpoints values of such scales. Whenever possible, metanalyses comparing clozapine to other specific atypical antipsychotic were performed. Effect sizes were shown as relative risks (RR) or weighted or standardized mean differences (MD), with 95% confidence intervals. The fixed effect model was used, unless studies were considered heterogeneous. Sensivity analyses were performed with the exclusion of studies which had included intolerant patients along with true refractory patients. RESULTS: Eleven RCTs were included, figuring 1182 patients, with 12 comparisons between clozapine and other atypical antipsychotics: four with risperidone, one with ziprasidone, and seven with olanzapine. Considered as a group, it was not possible to determine different effect sizes between atypical antipsychotics and clozapine for any general measure of psychotic symptoms. Pooled mean change and endpoint PANSS and BPRS scores metanalysis presented a zero mean difference (MD=0.00, CI95%= -0.12, 0.11). Atypical antipsychotics were shown to be marginally superior to clozapine for negative symptoms, measured by PANSS negative symptoms subscale endpoint scores (DM= 1.96, CI95%= -3.44, -0.48). Studies which compared clozapine to olanzapine had relatively high mean final olanzapine doses (means ranging from 17.2 mg/d to 33.6 mg/d), what might have influenced the results. CONCLUSIONS: Atypical antipsychotics, particularly high dose olanzapine, can represent an alternative therapeutic approach to patients with refractory schizophrenia

Class of 2015 Abstract / Objectives: The study aimed to increase EPS risk factor assessment when prescribers order prophylactic anticholinergics with antipsychotics. An evidence-based pharmacist checklist card was developed to aid in this decision making process. Methods: A retrospective chart review of patients admitted to the acute inpatient psychiatry units at an academic medical center was conducted to determine baseline prophylactic anticholinergic prescribing habits over a two-month period. Charts were included if the patient was at least 18 years old and ordered at least one scheduled antipsychotic during the admission. An educational intervention session introduced the pharmacist checklist card and shared baseline findings. Post-intervention data was collected during a two-month period following the intervention. The percentage of prophylactic anticholinergic orders based upon pharmacist checklist card parameters pre and post-intervention was analyzed using chi-square test. Results: There was a significant decrease in the total percentage of orders for prophylactic anticholinergics from 72.7% in the pre-intervention period to 50.8% in the post-intervention period (p<0.001). Significant changes in the percentage of orders for prophylactic anticholinergics were also found for patients at no-to-low risk for EPS (56.4% versus 31.8%, p=0.014) and at low-to-moderate risk for EPS (79.6% versus 50.8%, p=0.003). There were no significant changes observed in the percentage of orders for prophylactic anticholinergics for patients at moderate-to-high risk for EPS. A lower percentage of patients prescribed a prophylactic anticholinergic experienced adverse effects in the post versus the pre-intervention period (52.31% versus 75.27%, p=0.003). Conclusions: Significant differences were found between pre and post-intervention anticholinergic medication prescribing habits. This suggests that increased patient risk factor assessment in the form of a pharmacist checklist card is effective in decreasing orders for prophylactic anticholinergic medications not clinically indicated and reducing the incidence of adverse effects.

Objectives: This retrospective analysis was conducted to derive national estimates of typical, atypical, and combination (typical-atypical) antipsychotic use and to examine factors associated with their use at adult (age ≫-18 years) ambulatory care visits by patients with mental health disorders in the United States. Methods: Data on adult visits with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for a mental health disorder were extracted from the office-based National Ambulatory Medical Care Survey and the outpatient facilitybased National Hospital Ambulatory Medical Care Survey from 1996 through 2003. The visits were categorized according to whether use of a typical, atypical, or combination antipsychotic was mentioned (either prescribed, supplied, administered, ordered, or continued at the visits). Total weighted visit estimates, weighted visit percentages, and 95% CIs were calculated across the 3 types of visit groups. Bivariate analysis was performed on the association between selected characteristics and the 3 visit groups. Multivariate logistic regression was performed on factors associated with atypical versus typical antipsychotic use. Results: During the 8-year period, there were an estimated 47.7 million adult ambulatory care visits involving a mental health disorder and mention of an antipsychotic (weighted percent: 0.83%; 95% CI, 0.73-0.93). From 1996/1997 to 2002/2003, visits involving atypical and combination antipsychotics increased by 195% and 149%, respectively, and visits involving typical antipsychotics decreased by 71%. Men, blacks, and those with public insurance made more visits in which combination antipsychotics rather than typical or atypical antipsychotics were mentioned. Relative to typical or combination antipsychotic visits, more atypical antipsychotic visits involved antide-pressants (weighted percent: 61.23% atypical, 37.29% typical, and 38.32% combination). Fewer atypical antipsychotic visits compared with typical or combination antipsychotic visits involved psychotic disorders (weighted percent: 32.94%, 51.23%, and 69.93%, respectively) and medications for extrapyramidal symptoms (weighted percent: 6.69%, 29.95%, and 36.64%). In multivariate analyses controlling for sex, race, diagnosis of schizophrenia, region, diagnosis of anxiety, and recent years, atypical versus typical antipsychotic use was significantly less likely at visits by those aged 41 to 64 years compared with those aged 18 to 40 years (adjusted odds ratio [OR] = 0.63; 95% CI, 0.47-0.84; P = 0.002); significantly less likely at visits by those with public compared with private insurance (Medicare OR = 0.59 [95% CI, 0.40-0.88], P = 0.010; Medicaid OR = 0.44 [95% CI, 0.28-0.69], P < 0.001); and significantly more likely at visits associated with depression compared with those not associated with depression (OR = 1.92; 95% CI, 1.26-2.93; P = 0.003) and those associated with bipolar disorder compared with those not associated with bipolar disorder (OR = 2.10; 95% CI, 1.32-3.36; P = 0.002). Conclusions: This retrospective analysis found more atypical than typical or combination antipsychotic use at US ambulatory care visits by adults with mental health disorders other than schizophrenia or psychoses in the period studied. Atypical versus typical antipsychotic use was significantly less likely at visits by adults aged 41 to 64 years and those with public insurance, but significantly more likely at visits by those with depression or bipolar disorder.

Background. Little is known about longitudinal prescribing practices for psychoactive medications for individuals with intellectual disabilities and developmental disabilities (IDDD) who are living in community settings. Methods. Computerized pharmacy records were accessed for 2344 community-based individuals with IDDD for whom a total of 3421 prescriptions were written during a 17-month period of study. Forty-two psychoactive medications were rank ordered in terms of prescription frequency. Results. Fifty-two per cent (52%) of all prescriptions written during the study period were for psychoactive medications. Anticonvulsant, antipsychotic and antidepressant medications were the most commonly filled prescriptions among psychoactive medications. Sixty per cent (62%) of the study population was given prescriptions for more than one psychoactive medication and 36% received three or more psychoactive medications. During the study period there was a statistically significant increase in prescriptions filled for olanzapine, risperidone, valproic acid, and clonazepam whereas prescriptions filled for thioridazine, haloperidol, and benzotropine showed a significant decline (P < 0.05-0.001). Distribution of psychoactive drug class by age showed that the majority of prescriptions were filled for individuals between 20 and 50 years with the exception of prescriptions for psychostimulants which peaked for individuals prior to 20 years. Conclusions. (1) Analysis of pharmacy billing records provides a method for assessing prescribing patterns of psychoactive medications in community-based individuals with IDDD. (2) Polypharmacy for psychoactive medications is prevalent in this setting. (3) The second-generation antipsychotic medications are prominently represented by an increasing number of filled prescriptions during the study period.

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Thesis (Ph. D.)--West Virginia University, 2005. / Title from document title page. Document formatted into pages; contains xvii, 327 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 311-323).

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.

Dissertation (PhD)--Stellenbosch University, 2003. / ENGLISH ABSTRACT: Although schizophrenia is traditionally viewed as an illness with a very poor prognosis, research over the last few years indicates that early intervention may substantially improve the long-term outcome of this disorder. Several studies suggest that patients with first-episode psychosis (FEP) are more sensitive to, and require lower doses of antipsychotic medications than patients with more chronic forms of illness. However, the optimal dose of first-generation anti psychotics in patients with FEP has not been explored extensively and continues to be a controversial subject. This study evaluated the efficacy and safety of low-dose haloperidol in a South African cohort with FEP. The study was conducted in two phases: Phase 1 was an open-label, naturalistic study of 57 subjects with FEP who were commenced on 1mg of haloperidol for 4 weeks, after which gradual escalation of doses were allowed, if required. Subjects who failed to respond at haloperidol 10mg per day were switched to thioridazine. Failure to respond to thioridazine 600mg per day was interpreted to indicate treatment resistance. These subjects were then commenced on clozapine. The principal finding of this phase of the study was that the majority of subjects could be stabilized and maintained on very low doses of haloperidol (1.7 ± 1.0 mg/day at 12 months and 1.3 ±0.8 mg/day at 24 months). Ratings for extra-pyramidal side-effects did not increase significantly from baseline over the duration of the study, except in the case of tardive dyskinesia (TD), where a substantial number of subjects (12.3%) developed TD within 12 months of starting treatment. Phase 2 of the study was a double-blind, randomized controlled trial of low-dose (2mg/day) versus "standard dose" (8mg Iday) haloperidol. Forty subjects were included in this phase of the study; 20 in each treatment arm. The main finding was that there were no significant differences in treatment reponse between the two treatment groups. There were, however, significant differences between the two treatment groups in extrapyramidal side effects (EPSE), with the 8mg per day group exhibiting significantly higher levels of EPSE than the 2mg per day group. This was manifested by significant differences in scores on the Extrapyramidal Symptom Rating Scale (ESRS) and the Simpson-Angus Rating Scale. Furthermore, subjects in the 8mg haloperidol per day group required significantly higher doses of anticholinergic medication and had significantly higher mean levels of prolactin at the end of the study period. This study indicates that a majority of subjects with first-episode psychosis can be treated and maintained successfully with very low doses of haloperidol. It also shows that low-dose treatment is as effective as, and better tolerated than, "standard" doses. Despite the success with the low-dose treatment, however, there was still a much higher than expected incidence of tardive dyskinesia, a serious and potentially irreversible side-effect of neuroleptic treatment. / AFRIKAANSE OPSOMMING: Hoewel skisofrenie tradisioneel gesien is as 'n siekte met 'n uiters swak prognose, dui navorsing oor die afgelope jare daarop dat vroeë ingryping die langtermynuitkoms van hierdie toestand drasties mag verbeter. Resultate van verskeie studies dui daarop dat pasiënte met eerste-episode psigose (EEP) nie net meer sensitief is vir antipsigotiese middels nie, maar ook laer dosisse daarvan benodig tydens behandeling as pasiënte met meer kroniese vorms van psigotiese siekte. Desondanks is die kwessie van die korrekte dosis van eerste generasie antipsigotika in hierdie groep nog onvolledig nagevors en bly dit 'n omstrede onderwerp. Hierdie studie het ten doel gehad om die effektiwiteit en veiligheid van lae dosis haloperidol in 'n Suid-Afrikaanse populasie van pasiënte met EEP te evalueer. Die studie is uitgevoer in twee fases: Fase 1 was 'n oop, naturalistiese studie van 57 pasiënte met EEP wat aanvanklik behandel is met 1mg haloperidol per dag vir 4 weke, waarna geleidelike verhoging van dosisse toegelaat is, soos nodig. Diegene wat nie bevredigende respons getoon het op haloperidol 10mg per dag nie, is oorgeskakel na tioridasien. Ontoereikende respons teen 600mg/dag tioridasien is geïnterpreteer as 'n aanduiding van behandelingsweerstandigheid en behandeling met klosapien is begin. Die belangrikste bevinding van hierdie fase van die studie was dat die meerderheid pasiënte gestabiliseer en in stand gehou kom word op baie lae dosisse haloperidol (1.7 ± 1.0 mg/dag op 12 maande en 1.3 ±0.8 mg/dag op 24 maande). Metings van ekstra-piramidale newe-effekte (EPNE) het nie beduidend toegeneem oor die duur van die studie nie, behalwe in die geval van tardiewe diskinese (TO), waar 'n beduidende aantal pasiënte (12.3%) TO ontwikkel het binne 12 maande na aanvang van behandeling. Fase 2 van die studie was 'n dubbelblinde, ewekansig gerandomiseerde studie waarin behandeling met lae dosis haloperidol (2mg/dag) vergelyk is met "standaard" dosis haloperidol (8mg/dag). Veertig pasiënte is ingesluit in hierdie fase van die studie, 20 in elke behandelingsarm. Die hoofbevinding was dat daar geen beduidende verskille in respons op behandeling was tussen die twee groepe nie. Daar was egter beduidende verskille in EPNE, waar die 8mg/dag groep beduidend hoër vlakke van EPNE gehad het as die 2mg/dag groep. Hierdie verskil in EPNE is aangedui deur 'n statisties beduidende verskil in tellings op die Extrapyramidal Symptom Rating Scale (ESRS) en die Simpson- Angus Rating Scale. Verder het pasiënte in die 8mg/dag groep beduidend hoër dosisse antikolinerge medikasie benodig en ook hoër gemiddelde prolaktienvlakke gehad teen die einde van studie. Hierdie studie dui dus daarop dat die meerderheid van pasiënte met EEP suksesvol behandel en in stand gehou kan word met baie lae dosisse haloperidol. Die studie wys ook daarop dat behandeling met lae dosisse net so effektief is en beter verdra word as behandeling met "standaard" dosisse. Ten spyte van die suksesvolle gebruik van lae dosisse medikasie het die studie egter ook getoon dat daar "n baie hoër as verwagte insidensie was van TO, "n emstige en potensieelonomkeerbare newe-effek van neuroleptiese behandeling.

Thesis (PhD)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Prospective, longitudinal clinical studies in first-episode schizophrenia have become relatively commonplace over the past two decades or more and have provided a wealth of useful information regarding the clinical presentation, treatment, course and outcome of the illness. However, there remain several unanswered questions. The majority of the studies have been conducted in upper income countries using often costly medication with heterogeneous samples. While the overall outcome of patients showed some progress, there is room for improvement yet. The overall aim of the dissertation was to study the clinical, biological and functional aspects of outcome in first episode schizophrenia in a resource constrained setting. We conducted a prospective, non-comparative, longitudinal study over 12 months assessing the efficacy and tolerability of a cost effective, long-acting injectable antipsychotic (LAI; flupenthixol decanoate) combined with an assertive monitoring program (AMP) among first-episode schizophrenia patients. Efficacy was measured by examining rates of response, remission and relapse, as well as quality of life and social and occupational functioning. Tolerability of our intervention was assessed by measuring extrapyramidal symptoms, and weight and metabolic changes. We also examined the evolution of treatment refractoriness by studying the rates of non-response, and other associated predictor and outcome features. We found high rates of acceptance and adherence to the LAI and AMP. Seventy percent of our patients completed the 12 months of treatment. Treatment response was achieved by 82% of the participants and 60% achieved remission. Although 19% of our patients relapsed, the majority of the relapses were mild and did not require hospitalisation. Patients experienced significant quality of life and social and occupational functioning improvements. We found mild rates of extrapyramidal effects, present in only a third of our cohort. The majority of the extrapyramidal effects were treated with anticholinergics or propranolol. Only 3% of our patients developed transient dyskinesia over the duration of the study. However, our cohort gained considerable weight, with statistically significant increases in BMI (p< .0001) and waist circumference (p=0.0006). Our cohort also experienced significant deleterious changes to their lipid profiles. Of particular concern was the increase in triglycerides (p=0.03) and a significant decrease in high density lipoprotein (p=0.005) leading to a 91% increase in the triglyceride/high density lipoprotein ratio. With regards to emerging treatment refractoriness, 12% of our patients met our pre-defined criteria for non-response. Non-responders were younger and at baseline showed more prominent disorganised symptoms, poorer social and occupational functioning, poorer quality of life for psychological, social and environmental domains, more prominent neurological soft signs (NSS), and lower BMI. At endpoint the non-responders were characterised by higher levels of symptomatology in all domains; poorer functional outcome, poorer quality of life and greater cognitive impairments. They also had more prominent NSS and a lower BMI. The strongest predictors of non-response were prominent baseline NSS and poor early (7 weeks) treatment response. In conclusion, the combination of an LAI with an AMP may be an effective and safe intervention in firstepisode schizophrenia, and may be particularly suitable for resource-constrained settings. The risk of weight gain and metabolic syndrome associated with antipsychotic treatment in first-episode schizophrenia are not restricted to second generation antipsychotics and low-potency first-generation antipsychotics. Ensuring effective treatment for first episode schizophrenia patients is a global problem, and likely to be under-recognised in LMICs. / AFRIKAANSE OPSOMMING: Oor die afgelope twee dekades het toenemend meer longitudinale kliniese studies, wat eerste episode skisofrenie bestudeer, die lig gesien. Die studies het ‘n magdom van waardevolle inligtng oor die kliniese voorkoms, behandeling, verloop en uitkomste van die siekte opgelewer. Die meerderheid van die studies is egter in hoë inkomste ontwikkelde lande gedoen met pasiënte wat duur medikasie gebruik en hoofsaaklik in heterogene steekproewe. Alhoewel dit blyk uit hierdie studies dat daar oor die algemeen vordering gemaak word ten opsigte van die behandeling van pasiënte is daar steeds ‘n gebrek aan voldoende inligting oor die onderwerp veral in minder gegoede, ontwikkelende lande. Die oorhoofse doel van hierdie proefskrif is om binne ‘n hulpbron beperkte konteks die kliniese, biologiese en funksionele aspekte van pasiënt -uitkomste in eerste episode skisofrenie te ondersoek. Ons het ‘n longitudinale studie gedoen waarin ons die effektiwiteit en toleransie van ‘n enkele antipsigotiese medikasie vir 12 maande nagevors het. Die medikasie wat ons ondersoek het, is flupenthixol decanoate en word deur ‘n inspuiting gegee en die medikasie word dan geleidelik deur die liggaam geabsorbeer. As deel van die behandeling het ons pasiënte ook streng gemonitor. Ons het die effektiwiteit van die behandeling gemeet nagelang van hoe pasiënte reageer op die behandeling, hoeveel pasiënte in remissie gaan en terugval, en ook pasiënte se kwaliteit van lewe en hulle sosiale en beroepsfunksionering. Ons het toleransie gemeet nagelang van pasiënte se gewig en metaboliese verandering sowel as die voorkoms van medikasie geïnduseerde newe-effekte. Verder het ons pasiënte wat nie op medikasie gereageer het nie ondersoek sowel as die aspekte wat moontlik hiernee verband hou. Ons het bevind dat die meerderheid van pasiënte hulle medikasie getrou geneem het en ook die streng monitering aanvaar het. Sewentig persent van die pasiënte het hulle 12 maande behandeling voltooi, 82% het op die medikasie gereageer en 60% het in remissie ingegaan. Alhoewel 19% van die pasiënte teruggeval het, was dit nie so ernstig dat ons hulle moes hospitaliseer nie. Pasiënte het beduidende verbetering ten opsigte van hulle kwaliteit van lewe en sosiale en beroepsfunksionering getoon. Ons het slegs ‘n gematigde mate van medikasie geïnduseerde newe-effekte opgemerk en alleenlik by ‘n derde van die kohort. In die meerderheid van gevalle het ons die newe-effekte met anticholinergics of propranolol behandel. Slegs 3% van die pasiënte het gedurende die verloop van 12 maande die kondisie transient dyskinesia ontwikkel. Ongelukkig het ons kohort geweldig baie gewig opgetel en die toename in pasiënte se BMI (p< .0001) en middellyf omtrek (p=0.0006) was statisties beduidend. Ons het ook bevind dat veranderinge in ons kohort se lipied profiele kommerwekkend is veral as in ag geneem word dat die toename in trigliseriede (p = 0,03) en die beduidende afname in die hoë digtheid lipoproteïen (p = 0,005) gelei het tot ‘n 91% verhoging in trigliseriede: hoë digtheid lipoproteïen verhouding.