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Autologous CD19-directed chimeric antigen receptor (CAR)-T cells have shown unprecedented efficacy in children with relapsed/refractory B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). However, patients either relapsing after allogeneic hematopoietic stem cell transplantation (allo-HSCT), or displaying profound lymphopenia and/or with rapidly progressing disease often cannot access autologous products. These hurdles may be overcome by allogeneic, donor-derived CAR-T cells. We tested donor-derived T-cells transduced with a 2nd-generation (4.1BB) CD19-CAR for treatment of patients with BCP-ALL, in a hospital exemption setting. Two constructs were tested: a retroviral construct incorporating the suicide gene inducible caspase-9 (CD19-CAR-Retro_ALLO) first and then a lentiviral construct and an automated, Prodigy®-based, manufacturing process (CD19-CAR-Lenti_ALLO). Thirteen children/young adults received ALLO-CAR T-cells between 03/2021 and 10/2022. Doses ranged between 1,0×106 and 3,0×106 CAR T-cells/kg. The toxicity profile was comparable to that of autologous CAR-T cells, characterized mainly by cytopenia, CRS (maximum grade 1) and grade 2 ICANS. One case of acute graft-versus-host disease (GvHD) occurred and was rapidly controlled by steroids and ruxolitinib. None of the other patients, including 3 infused with ALLO-CAR T cells from an HLA-haplo-identical donor, experienced GvHD. Two patients received ALLO-CAR T-cells before HSCT and showed a significant expansion of CAR T cells, without any sign of GvHD. All patients obtained complete remission (CR) with negativity of minimal residual disease in the BM; with a median follow-up of 12 months (range 5-21), 8/13 patients maintain CR. Allogeneic anti-CD19 CAR-T cells can effectively treat highly-refractory BCP-ALL relapsing after alloHSCT, without showing increased toxicity as compared to autologous CAR T cells.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a ‘later stage handoff’ to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.

The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first-or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplanta-tion and be definitive therapy versus those in whom it provides a more effective bridge to hae-matopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully huma-nised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prior-itisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary medi-astinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this pop-ulation. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials.CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell ther-apies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success.The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies.Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regu-latory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially impor-tant as these are very expensive therapies.The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies. 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This paper reports 17 years of passive safety surveillance of routine use of the pediatric hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenza...

This paper reports 17 years of passive safety surveillance of routine use of the pediatric hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Global post-licensure passive surveillance data collected in GSK's central safety database since DTPa-HBV-IPV/Hib's launch (2000) are described.The most common spontaneously reported adverse events (AEs) after DTPa-HBV-IPV/Hib vaccination in children were fever (reporting rate: 7.74/100,000 doses distributed), crying (2.62/100,000), injection site erythema (1.87/100,000) and swelling (1.28/100,000). A review of extensive limb swelling did not reveal any safety concerns. An observed-to-expected analysis did not show an increased risk of sudden death after DTPa-HBV-IPV/Hib vaccination, in line with previous observations. The analyses confirmed that increases in spontaneous reporting proportions of convulsions with/without fever and hypotonic-hyporesponsive episodes after co-administration of DTPa-HBV-IPV/Hib and 13-valent pneumococcal conjugate vaccine remained small and their clinical significance unknown. The most common vaccination errors were mistakes in the vaccination schedule. Reporting of preparation errors (mostly reconstitution) was low and did not impact the vaccine's benefit-risk profile.Seventeen years of post-licensure experience confirm confidence in the safety profile of DTPa-HBV-IPV/Hib in routine use, with a favorable benefit-risk profile in infants and toddlers.

Combination vaccines improve vaccine uptake and open the infant immunization space for additional vaccines. Hexavalent vaccines have been marketed since 2000. Infanrix hexa (combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine, DTPa-HBV-IPV/Hib, GSK) is longest on the market, providing 16 years post-marketing experience. Each DTPa-HBV-IPV/Hib vaccine component is licensed alone and/or in smaller combination vaccines. Programmatic considerations sometimes require an interchange between vaccines due to unavailability, program change or mixed schedules (when the number of required antigens differs across scheduled primary vaccination visits).Immunogenicity and safety data from 11 GSK-sponsored clinical trials support the interchangeability of DTPa-HBV-IPV/Hib within the same vaccines family, and use of DTPa-HBV-IPV/Hib in mixed primary vaccination schedules.Data show acceptability of interchange of DTPa-HBV-IPV/Hib with other products within the same vaccines family and its use in mixed immunization schedules. This aligns with WHO recommendations that vaccines of the same family from the same manufacturer be used to complete the infant vaccination schedule. Interchangeability and suitability for use in mixed schedules is of interest for policy-makers/providers in the framework of vaccination recommendations as it provides flexibility. Given the complexity of larger combination vaccines, interchangeability or sequential use needs careful assessment.

Introduction This phase I first-in-human clinical study assesses the safety and preliminary efficacy of a CD19-directed, CAR (4-1BBz) gene-modified, autologous T-cell immunotherapy (MB-CART19.1) intended for use in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) and Non-Hodgkin lymphoma (NHL). The study also evaluates the feasibility of a hybrid manufacturing model, combining central and academic manufacturing capabilities with central QP oversight. Methods MB-CART19.1 is evaluated in a Phase I (EudraCT 2017-002848-32) multi-center, open label, dose escalation trial enrolling 33 to 48 patients in three disease cohorts, defined by disease biology and age. Pediatric (1-17 years) and adult patients are eligible if diagnosed with relapsed/refractory (r/r) CD19-expressing B-cell ALL or B-cell high-grade and low-grade (adults) NHL, including chronic lymphocytic leukemia (CLL). Enrollment is still ongoing. The starting material, a fresh patient leukapheresis product, is enriched for CD4/CD8 T-cells, transduced with a lentiviral vector (LV) and expanded using the CliniMACS Prodigy System allowing a high degree of control and consistency of the manufacturing process in both a central and decentralized facilities. MB-CART19.1 is presented as fresh cellular dispersion for single infusion and undergoes central release. Subjects undergo lymphodepletion with fludarabine (25 mg/m 2 daily for 3 days) and cyclophosphamide (1000 mg/m 2 on day -3). Dose escalation includes 3 dose levels (DL) 5x10 5 (DL I), 1x10 6 (DL II), 3x10 6 (DL III) CAR T cells/kg BW, respectively, and a safety dose level 0. The primary objective is to determine the recommended dose of MB-CART19.1. Secondary objectives are preliminary efficacy parameters evaluation of as well as CART persistence. Results Disease cohort I: pediatric ALL and aggressive NHL, 1-17 years. Up to the data lock point for interim analysis (DLP, 02 June 2021), 9 pediatric ALL patients were treated, 6 at DL I and 3 at DL II. All 9 patients completed the 28 days safety follow-up. At DL I, 5 of 6 patients experienced CRS (4 grade I-II, 1 grade III,) starting 5 to 7 days after IMP infusion. Two CRS cases were managed with tocilizumab and resolved within 1-2 weeks. 1 patient developed signs of neurotoxicity (grade IV seizure) concurrently with grade II CRS, which was effectively managed and fully resolved within 48 hours. The event was evaluated as DLT and led to the extension of the dose group from 3 to 6 patients. No further neurotoxicities occurred. Four of 6 patients treated at DL I finished the active part of the trial (12 months after administration of IMP) in CR-MRD and entered the long term follow-up. Two patients had CD19-negative relapses 4 and 10 months post MB-CART19.1 infusion. At DL II, 1 patient completed the 6 months follow up in ongoing CR, and 2 patients relapsed. Disease cohort II adult ALL: Up to the DLP, 4 adult ALL patients were treated at DL I. 1 patient died due to progression of disease on day 20 after the IMP infusion. All 4 adult patients experienced a grade I or II CRS all cases were reversible within 1-2 weeks , 1 patient received tocilizumab One patient developed neurologic symptoms (grade III visual impairment and grade III muscle weakness right-sided) with onset 41 and 72 days after administration of MB-CART19.1, respectively. 2 of the 3 patients who completed the safety follow-up finished the active part of the trial and entered the long-term follow-up, both in molecular CR up to Month 6. Disease cohort III adult NHL/CLL: 4 patients were enrolled with the starting dose of 1x10 6 CAR+ cells/kg (DL II). 1 patient experienced grade III CRS and was treated with tocilizumab. 3 patients completed the 28 days safety follow up. One patient with CLL achieved a CR, which is maintained at 6 months. Another CLL patient was in PR at the assessment visit Day 28. Data from the 2 other patients, 1 with MCL and 1 with DLBCL were in PR at month 3. Later data is not yet available. Conclusions 18 of 19 patients completed the follow-up safety period of 28 days defined as observation period for dose limiting toxicity (DLT). One DLT was observed as well as 3 grade III CRS events and 1 grade III neurological event. Early efficacy results are very encouraging. Longer follow-up will establish whether treatment results in durable responses. The hybrid manufacturing model provides flexibility and a timely delivery of the fresh drug product to the patients Disclosures Hanssens: Miltenyi Biomedicine GmbH: Current Employment. Stelljes: MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Yakushina: Miltenyi Biomedicine GmbH: Current Employment. Holtkamp: Miltenyi Biomedicine GmbH: Current Employment. Assenmacher: Miltenyi Biotec: Current Employment. Jurk: Miltenyi Biotec: Current Employment. Rauser: Miltenyi Biomedicine GmbH: Current Employment. Schneider: Employee of Lentigen Technology, a Miltenyi Biotec Company: Current Employment. Rossig: AdBoards by Amgen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS and Celgene: Honoraria.

Background: Vaccinating infants against hepatitis B virus (HBV) is the most effective way of preventing the disease. However, since HBV exposure can increase during adolescence, it is essential that antibody persistence is maintained. We evaluated the antibody persistence and immune memory against hepatitis B, in 12-13 y olds who had received complete primary + booster vaccination with diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus/Haemophilus influenza type b (DTPa-HBV-IPV/Hib) vaccine in infancy. Methods: Open phase-IV study conducted at 12 centers in Germany [NCT02052661]. Adolescents aged 12-13 y, vaccinated with 4 doses of DTPa-HBV-IPV/Hib (Infanrix hexa™, GSK Vaccines) in infancy, received a single challenge dose of monovalent pediatric hepatitis B vaccine (Engerix™-B Kinder; GSK Vaccines). Blood samples were taken before and 1-month post-challenge to measure anti-hepatitis B (anti-HBs) antibodies using a chemiluminescence immunoassay (seroprotection cut-off: ≥10 mIU/ml). Post-challenge adverse events (AEs) were monitored. Results: 300 subjects were vaccinated; of 293 subjects in the ATP immunogenicity cohort, 60.5% had pre-challenge anti-HBs antibodies ≥10 mIU/ml, which rose to 97.6% post-challenge (≥100 mIU/ml in 94.1%). An anamnestic response was seen in 96.5% subjects. A 150-fold increase in antibody geometric mean concentrations was observed (22.4 to 3502.6 mIU/ml). Pain (44%) and fatigue (24.3%) were the most frequent solicited local and general AEs, respectively; 14.7% subjects reported unsolicited symptoms during the 31-day post-vaccination period. Two vaccine-unrelated serious AEs occurred. Conclusion: Vaccination with DTPa-HBV-IPV/Hib in infancy induces sustained seroprotection and immune memory against HBV, as shown by the strong anamnestic response to the hepatitis B vaccine challenge in 12-13 year-old adolescents.

Pregnancy and the postpartum period are associated with elevated risks to both mother and infant from infectious disease. Vaccination of pregnant women, also called maternal immunization, has the potential to protect pregnant women, foetuses and infants from several vaccine-preventable diseases. Maternal immunoglobulin G antibodies are actively transferred through the placenta to provide passive immunity to new-borns during the first months of life, until the time for infant vaccinations or until the period of greatest susceptibility has passed. Currently, inactivated influenza, tetanus, and pertussis vaccines are recommended during pregnancy in many countries, but other vaccines may also be administered to pregnant women when risk factors are present. Several new vaccines with a specific indication for use during pregnancy are under development (e.g. respiratory syncytial virus and group B streptococcus vaccines). Years of experience suggest that maternal immunization against influenza, tetanus or pertussis has an acceptable safety profile, is well tolerated, effective and confers significant benefits to pregnant women and their infants. This review describes the principles of maternal immunization and provides an update of the recent evidence regarding the use and timing of maternal immunization. Finally, the barriers preventing wider vaccination coverage and the current limitations in addressing these are also described (Supplementary Material).Key messagesMaternal immunization gives pregnant women greater protection against infectious diseases; induces high levels of maternal antibodies that can be transferred to the foetus; and helps protect new-borns during their first months of life, until they are old enough to be vaccinated.Pregnant women and new-borns are more vulnerable to infectious diseases than the overall population; nevertheless, vaccination rates are often low in pregnant women.This review provides an update of the recent evidence regarding the use and timing of maternal immunization and describes the barriers preventing wider vaccination uptake and the current limitations in addressing these. Maternal immunization gives pregnant women greater protection against infectious diseases; induces high levels of maternal antibodies that can be transferred to the foetus; and helps protect new-borns during their first months of life, until they are old enough to be vaccinated. Pregnant women and new-borns are more vulnerable to infectious diseases than the overall population; nevertheless, vaccination rates are often low in pregnant women. This review provides an update of the recent evidence regarding the use and timing of maternal immunization and describes the barriers preventing wider vaccination uptake and the current limitations in addressing these.

The development of diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type b (Hib) conjugate vaccine combinations culminated with hexavalent vaccines, the largest, most complex vaccine combinations in the immunization calendar. Hexavalent vaccines are used widely in Europe and are co-administered with multiple other recommended vaccines. Hib immunogenicity may reduce when combined with acellular pertussis antigens, or in some co-administrations. We reviewed the epidemiology of H. influenzae disease in Europe aiming to evaluate the current level of Hib control and indirectly assess the effectiveness against Hib of GSK's hexavalent vaccine in 10 countries where it is/has been used almost exclusively. Areas covered: We reviewed surveillance data from the European Union Invasive Bacterial Infections Surveillance Network and the European Surveillance System database from 1999-2014 and extracted case and incidence/notification rates (per 100,000 population) of invasive H. influenzae disease. We included age and serotype/strains distribution among countries in the European Union/European Economic Area region that reported to the European Centre for Disease Prevention and Control surveillance system. Expert commentary: The impact of Hib vaccination in Europe is sustained, testifying to continued effectiveness against invasive Hib disease after the implementation of hexavalent vaccines into immunization programs, which, since 2006, has been almost exclusively GSK´s hexavalent DTPa-HBV-IPV/Hib vaccine.

Infants with history of prematurity (37 weeks gestation) and low birth weight (LBW,2500 g) are at high risk of infection due to functional immaturity of normal physical and immunological defense mechanisms. Despite current recommendations that infants with history of prematurity/LBW should receive routine immunization according to the same schedule and chronological age as full-term infants, immunization is often delayed.Here we summarize 10 clinical studies and 15 years of post-marketing safety surveillance of GSK's hexavalent vaccine (DTPa-HBV-IPV/Hib), a combined diphtheria-tetanus-acellular-pertussis-hepatitis-B-inactivated-poliovirus-Haemophilus influenzae-type-b (Hib) conjugate vaccine, when administered alone, or co-administered with pneumococcal conjugate, rotavirus, and meningococcal vaccines and respiratory syncytial virus IgG to infants with history of prematurity/LBW in clinical trials.At least 92.5% of infants with history of prematurity/LBW as young as 24 weeks gestation in clinical studies were seropositive to all vaccine antigens after 3-dose primary vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine, with robust immune responses to booster vaccination. Seropositivity rates and antibody concentrations to hepatitis B and Hib appeared lower in infants with history of prematurity/LBW than term infants. Between 13-30% of medically stable infants with history of prematurity developed apnea after vaccination with GSK's hexavalent DTPa-HBV-IPV/Hib vaccine; usually after dose 1. The occurrence of post-immunization cardiorespiratory events appears to be influenced by the severity of any underlying neonatal condition. Most cardiorespiratory events resolve spontaneously or require minimal intervention. GSK's hexavalent DTPa-HBV-IPV/Hib vaccine was well tolerated in co-administration regimens.GSK's hexavalent DTPa-HBV-IPV/Hib vaccine alone or co-administered with other pediatric vaccines has a clinically acceptable safety and immunogenicity profile when used in infants with history of prematurity/LBW for primary and booster vaccination. Additional studies are needed in very premature and very LBW infants. However, currently available data support using GSK's hexavalent DTPa-HBV-IPV/Hib vaccine to immunize infants with history of prematurity/LBW according to chronological age.

Objective Patients with schizophrenia are at increased risk of developing diabetes mellitus and cardiovascular disease. Furthermore, some atypical antipsychotics are associated with metabolic disturbances, which augment the risk for these comorbid conditions. In clinical trials, effects on metabolic parameters with aripiprazole are similar to those with placebo and superior to those with olanzapine, and the Schizophrenia Trial of Aripiprazole (STAR) demonstrated comparable efficacy of aripiprazole versus standard of care (SoC; physicians' selection of quetiapine, olanzapine, or risperidone). Method In this post hoc analysis, data from STAR were used to assess the risks of diabetes and coronary heart disease (CHD) in patients with schizophrenia. The Stern (San Antonio Heart Disease Study) and Framingham models, with modifications, were used to predict the risk of diabetes at 7.5 years and CHD at 10 years, respectively. Results Aripiprazole-treated patients had more favorable changes in lipids, glucose, and body weight versus SoC. In a subsample of patients who had fasting lipid and glucose test results, the Stern model predicted 23.4 fewer incidences of new-onset diabetes with aripiprazole versus SoC in a hypothetical 1000-patient cohort. The number needed to treat with aripiprazole to avoid 1 adverse outcome expected with SoC was 43. In the same population, the Framingham model predicted 3.9 fewer CHD events, with a number needed to treat with aripiprazole of 256. Conclusion Aripiprazole-treated patients had more favorable changes in metabolic parameters compared with SoC, leading to a reduced risk of diabetes and CHD, based on validated models.

Objectives: The presence of metabolic abnormalities is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of the metabolic abnormalities in disorders other than schizophrenia in which antipsychotic medication is part of routine treatment. Methods: Sixty consecutive patients with bipolar disorder (BD) at our university psychiatric hospital and affiliate services were entered in an extensive prospective metabolic study including an oral glucose tolerance test. The prevalence of the metabolic syndrome was assessed based on the National Cholesterol Education Program Adult Treatment Protocol (ATP-III) criteria, the adapted ATP-III criteria using a fasting glucose threshold of 100 mg/dL, and the recently proposed criteria from the International Diabetes Federation (IDF). Results: The analysis of 60 patients showed a prevalence of the metabolic syndrome of 16.7% (ATP-III), 18.3% (adapted ATP-III) and 30.0%) (IDF), respectively. A total of 6.7% of the patients met criteria for diabetes and 23.3% for pre-diabetic abnormalities. Conclusions: The metabolic syndrome and glucose abnormalities are highly prevalent among patients with BD. They represent an important risk for cardiovascular and metabolic disorders. Assessment of the presence and monitoring of metabolic abnormalities and its associated risks should be part of the clinical management of patients with BD.

ResumenAntecedentes.Los ensayos naturalistas sobre la efectividad de los antipsicóticos atípicos son necesarios para aportar una información más amplia sobre la eficacia, la seguridad y la tolerabilidad en pacientes con esquizofrenia tratados en un centro médico de la comunidad.Métodos.En este estudio multicéntrico abierto de 26 semanas, diversos pacientes con esquizofrenia, que necesitaron un cambio en la medicación antipsicótica porque no toleraban bien la medicación actual y/o porque los síntomas clínicos no estaban bien controlados, se aleatorizaron para recibir aripiprazol o un tratamiento estándar (TE) con un antipsicótico atípico (por ejemplo, olanzapina, quetiapina o risperidona en función del juicio del investigador sobre el tratamiento óptimo de cada paciente individual y la respuesta previa del paciente a la medicación antipsicótica). El objetivo principal fue comparar la efectividad de un tratamiento de 26 semanas con aripiprazol con el TE, medido por la puntuación total del Cuestionario de Evaluación del Investigador (IAQ) en la última observación arrastrada (UOA) de la semana 26 (variable primaria), una medida validada que controla el alivio o el empeoramiento de 10 síntomas clave asociados con la psicopatología de la esquizofrenia y los efectos secundarios del tratamiento antipsicótico. Los objetivos secundarios fueron evaluar la efectividad usando las escalas Impresión Clínica Global - Mejoría Global (CGI-I) e Impresión Clínica Global - Gravedad de la Enfermedad, para evaluar el tiempo transcurrido hasta la suspensión del tratamiento, la preferencia del paciente respecto a la medicación, y la calidad de vida y la tolerabilidad de aripiprazol comparado con el TE.Resultados.El tratamiento con aripiprazol (n=268) fue significativamente más eficaz que el TE (n = 254; P < 0,001; UOA de la semana 26), evidenciado por la puntuación IAQ total, desde la semana 4 (primera fase de evaluación) y se mantuvo hasta la semana 26. Una relación similar se demostró en los pacientes que terminaron el estudio (análisis de casos observados); aripiprazol se asoció con una efectividad significativamente mayor en todas las fases de evaluación con un mayor efecto diferencial de TE con el tiempo. Los pacientes tratados con aripiprazol también tuvieron mejorías significativamente mayores en la escala CGI-I (tasa de rspuesta, P = 0,009 en la UOA de la semana 26), y en la calidad de vida (puntuación total en la escala de Calidad de Vida; P < 0,001 en la semana 26). Además, una proporción significativamente mayor de pacientes que recibieron aripiprazol calificaron la medicación del estudio como “mucho mejor” en la escala del Cuestionario de Preferencias de Medicación (POM) que la medicación anterior al estudio comparados con los pacientes tratados con TE (P < 0,001; semana 26). El tiempo hasta la suspensión del tratamiento y las tasas de suspensión debidas a episodios adversos fueron similares en los dos grupos de tratamiento. La incidencia de pacientes con uno o varios síntomas extrapiramidales (por ejemplo, acatisia, distonía, episodios parkinsonianos y episodios residuales) fue mayor en los pacientes que recibieron aripiprazol comparados con los pacientes tratados con TE (13,5% frente a 5,6%); sin embargo, una proporción mayor de pacientes del grupo TE tuvo un aumento de peso clínicamente significativo (21,2% frente a 7,3% para aripiprazol) y de las concentraciones séricas (potencialmente importantes desde el punto de vista clínico) de colesterol total, colesterol de lipoproteínas de baja densidad, triglicéridos y prolactina comparados con los pacientes que recibieron aripiprazol.Conclusiones.Aripiprazol es un antipsicótico atípico eficaz para el tratamiento de la esquizofrenia, que ha demostrado más efectividad que los fármacos estándar usados en este estudio en pacientes que necesitaban un cambio en la medicación antipsicótica.

Background: Metabolic abnormalities and weight gain are an important problem in patients with schizophrenia. An instrument to evaluate body image and self-esteem related to weight has recently been developed (B-WISE®). The first objective was to evaluate whether the findings of the original validation study could be confirmed in a European sample. The second objective was to explore the association of B-WISE® scores with the metabolic syndrome and glucose abnormalities. Methods: A Dutch translation of B-WISE® was tested in a large sample of patients with schizophrenia (n=300) who underwent an extensive metabolic screening. Results: The original findings with B-WISE® were confirmed in an independent sample. Scores on B-WISE® differed significantly as a function of BMI. Scores on B-WISE® also differentiated patients with and without the metabolic syndrome and glucose abnormalities. Patients experiencing a recent weight gain had lower self-esteem and poorer psychosocial adaptation. Conclusion: B-WISE® could be a useful instrument to evaluate the subjective psychosocial consequences associated with current weight and weight gain in patients with schizophrenia.

ResumenObjetivo.Una conferencia de consenso reciente ha propuesto directrices para el control de la diabetes en pacientes con esquizofrenia e identifica también la necesidad de estudios prospectivos a largo plazo.Método.Un estudio prospectivo a gran escala sobre los riesgos metabólicos de la medicación antipsicótica está en curso en la actualidad. En la línea de base, los pacientes pasan por una detección selectiva completa de laboratorio, ECG y una prueba oral de tolerancia a la glucosa (POTG). Se presentan los datos de línea de base sobre 100 pacientes que no eran diabéticos al incorporarse al estudio y se mantuvieron estables con la medicación durante 6 meses al menos.Resultados.Se encuentran anomalías de la glucosa en 22% de los pacientes en la línea de base. Un protocolo de control basado únicamente en la glucosa en ayunas no habría detectado a 63,6% de estos pacientes con anomalías clasificables de la glucosa en nuestra muestra. La insulina en ayunas y las medidas para la resistencia a la insulina tienen un elevado valor predictivo de anomalías posteriores en la POTG.Conclusión.Los problemas metabólicos están presentes con frecuencia ya en la línea de base en los pacientes con esquizofrenia tratados con antipsicóticos. Añadir la evaluación de la insulina en ayunas en un protocolo de control mejora la deteccíon de anomalías de la glucosa más tarde en una POTG.

The presence of the metabolic syndrome is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of the metabolic syndrome in European patients suffering from schizophrenia. Methods All consecutive patients with schizophrenia at our university psychiatric hospital and affiliate services were entered in an extensive prospective metabolic study including an oral glucose tolerance test. The prevalence of the metabolic syndrome was assessed based on the National Cholesterol Education Program criteria (NCEP, Adult Treatment Protocol, ATP-III), adapted ATP-III criteria using a fasting glucose threshold of 100 mg/dl (AHA) and on the recently proposed criteria from the International Diabetes Federation (IDF). Results The analysis of 430 patients showed a prevalence of the metabolic syndrome of 28.4% (ATP-III), 32.3% (ATP-III A) and 36% (IDF), respectively. The prevalence of the metabolic syndrome in our sample of patients with schizophrenia is at least twice as high compared to an age-adjusted community sample in Belgium. Conclusion The metabolic syndrome is highly prevalent among treated patients with schizophrenia. It represents an important risk for cardiovascular and metabolic disorders. Assessment of the presence and monitoring of the associated risks of the metabolic syndrome should be part of the clinical management of patients treated with antipsychotics.

Objective To assess the diagnostic properties of 2 different screening guidelines for the detection of diabetes in patients diagnosed with schizophrenia. Method Over a 2-year period (November 2003-November 2005), 415 patients with schizophrenia were screened with a full laboratory screening and a 75-g oral glucose tolerance test (OGTT). The sensitivity of 2 screening strategies was compared with the "gold standard": the OGTT. The 2 strategies were (1) assessing fasting glucose in all patients, as suggested by the American Psychiatric Association/ American Diabetes Association (APA/ADA), and (2) a screening strategy derived from the guidelines of the World Health Organization of assessing fasting glucose in all patients (step 1) and subsequently performing an OGTT in patients with impaired fasting glucose (step 2). Results Of the total sample, 6.3% (N = 26) met criteria for diabetes, resulting in a mean annual incidence of diabetes of 3.15% (6.3% incident cases/2 years). A screening based on the APA/ADA guidelines detected diabetes in 12 (46.2%) of the 26 cases identified by the OGTT. The proposed 2-step strategy detected 25 (96.2%) of 26 cases. Conclusion The data suggest a high incidence of diabetes in patients diagnosed with schizophrenia. However, the guidelines to detect diabetes as proposed by the APA/ADA did not sufficiently detect diabetes in this specific high-risk group. The alternative 2-step strategy was able to detect the vast majority of diabetes cases and should therefore be considered in the clinical routine of screening and monitoring patients with schizophrenia.

Background Mortality rates in patients with schizophrenia are double compared to those in the general population, with cardiovascular disease causing 50% of the excess. Lowering low-density lipoprotein (LDL) cholesterol is recognized as a primary target for the prevention of cardiovascular mortality according to the National Cholesterol Education Program-Adult Treatment Panel III. Use of lipid-lowering drugs such as statins is recommended when lifestyle changes are not sufficient to reach the LDL goal. The efficacy and safety of rosuvastatin treatment were evaluated in schizophrenic patients. Method 100 schizophrenic patients with severe dyslipidemia were identified. All were treated with antipsychotics. Fifty-two patients were treated with rosuvastatin and compared with 48 who did not receive statin treatment. All patients were screened for cardiovascular risk factors and examined at baseline. The effects of lipid-lowering medication on lipid profile, glucose homeostasis, and components of metabolic syndrome were evaluated at 3-month follow-up. The study began in 2003, and all data available until December 2005 are reported. Results After 3 months of statin therapy, a significant decrease in triglycerides, total cholesterol, LDL cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol and in associated ratios (LDL/HDL, total cholesterol/HDL) was observed. The difference was highly significant compared to patients not receiving statin treatment. No significant changes occurred in HDL cholesterol, body mass index and waist circumference, or glucose homeostasis. The only component of metabolic syndrome affected by statin therapy was the serum triglyceride level. Conclusion Rosuvastatin proved effective in the management of dyslipidemia in patients with schizophrenia treated with antipsychotics. More complex treatment may be required for associated metabolic disturbances.

Alfacalcidol (1-alpha-hydroxyvitamin D3 is a non-endogenous analog of vitamin D which can bypass the renal and intestinal regulatory mechanisms that control the production of calcitriol (1,25-hydroxyvitamin D3, the active form of vitamin D, D-Hormone). Alfacalcidol may be metabolized into calcitriol with a limited risk of hypercalcemia. Alfacalcidol and calcitriol have been evaluated in animal and human studies assessing their effects on bone mineral density and fracture rates. More recently, they have been shown to produce beneficial effects in muscle, immune system, and autoimmune diseases, including rheumatoid arthritis. This paper discusses the therapeutic efficacy of alfacalcidol in reports in which it has been proposed as an interesting alternative to vitamin D or calcitriol. Some recent findings about general metabolism and regulation of vitamin D and its analogs are discussed. The biological and clinical effects of alfacalcidol in post-menopausal osteoporosis are reviewed, followed by critical appraisal of its efficacy in preventing bone loss and falls in the elderly. The last two sections discuss the role of D-analogs in regulating the immune system, with particular regard to rheumatoid arthritis. The main results of this review show that alfacalcidol may have a wider range of therapeutic applicability, beyond simply restricting it to patients in hemodialysis or peritoneal dialysis with high serum levels of intact PTH.

Combination therapy includes the concomitant or sequential use of compounds sharing the same mode of action (e.g. two or more inhibitors of bone resorption) or with distinct pathways of activity (e.g. an inhibitor of resorption plus an anabolic agent). Combinatorial use of anti-resorptive agents may generate concerns, due to the risk of inducing oversuppression of bone turnover. However, if low doses of estrogen, used for the management of climacteric symptoms, are insufficient to normalize bone turnover, an addition of a bisphosphonate to HRT can prove to be useful to achieve this objective. Patients pre-treated with inhibitors of resorption, who have no full therapeutic response, are good candidates for the treatment with anabolic agents. The increase in bone turnover that follows the introduction of parathyroid hormone in patients treated with an anti-resorptive agent is similar to that observed in treatment-naive patients and the pattern of bone mineral density (BMD) increase is also identical, with the exception of a 6-month delay in the spine and hip BMD changes observed in prior alendronate-treated subjects. Current data discourage the concomitant use of alendronate and parathyroid hormone since the bisphosphonate appears to blunt, in men and women, the anabolic action of parathyroid hormone. Whether this also applies to other bisphosphonates or inhibitors of resorption remains unknown. The use of an inhibitor of bone resorption after completion of parathyroid hormone treatment seems an appropriate way to maintain the skeletal benefits gained during therapy. Longterm clinical studies, using fractures as an end-point should be initiated to better understand the clinical and pharmaco-economic interest of combination therapies in the management of osteoporosis.

IntroductionRecent research has shown that adiponectin levels in patients with schizophrenia vary similar to the general population. Moreover, antipsychotic medication may influence adiponectin levels, independent of metabolic parameters. We hypothesise different antipsychotics might vary in their effect on adiponectin levels independent of BMI and metabolic syndrome (MetS) status.Methods113 patients, with similar baseline demographic and metabolic characteristics, received either risperidone (n=54) or olanzapine (n=59). They were followed prospectively for 12 weeks. Adiponectin levels as well as general metabolic parameters were measured at baseline, 6 weeks and 12 weeks.ResultsWe observed a significant treatment by time interaction, showing an adiponectin increase in the risperidone treated patients and an adiponectin decrease in olanzapine treated patients. This effect was independent of BMI and the presence/absence of the metabolic syndrome. There was a significant association between fall in adiponectin and increase in waist circumference in the Olanzapine treated group (Figure 1).There was no change in HOMA-IR as a measure of insulin resistance in either group. ConclusionWe observed a differential effect of antipsychotic treatment (risperidone vs olanzapine) on adiponectin levels over time, independent of BMI (and MetS) suggesting an effect of olanzapine on adipose tissues, similar to what has been observed in animals models. The effects on adiponectin levels may partly explain the increased rates of obesity with Olanzapine.

ObjectiveA recent consensus conference has proposed guidelines for the monitoring for diabetes in patients with schizophrenia and also identifies the need of long-term prospective studies.MethodsA large scale prospective study on metabolic risks of antipsychotic medication is currently ongoing. At baseline, patients get a full laboratory screening, ECG and an oral glucose tolerance test (OGTT). Baseline data on 100 non-diabetic patients at study inclusion and stable on medication for at least 6 months are presented.ResultsGlucose abnormalities are found in 22% of patients at baseline. A monitoring protocol based only on fasting glucose would not have detected 63.6% of these patients with classifiable glucose abnormalities in our sample. Fasting insulin and measures for insulin resistance have a high predictive value for abnormalities late in the OGTT.ConclusionsAlready at baseline, metabolic problems are frequently present in patients with schizophrenia treated with antipsychotics. Adding assessment of fasting insulin in a monitoring protocol improves detection of glucose abnormalities late in an OGTT.

Second-generation antipsychotics (SGA), especially clozapine and olanzapine, are associated with an increased metabolic risk. Recent research showed that plasma adiponectin levels, an adipocyte-derived hormone that increases insulin sensitivity, vary in the same way in schizophrenic patients as in the general population according to gender, adiposity and metabolic syndrome (MetS). The aim of the present study was to investigate whether different SGAs differentially affect plasma adiponectin levels independent of body mass index (BMI) and MetS status. 113 patients with schizophrenia (65.5% males, 32.3years old) who were free of antipsychotic medication were enrolled in this open-label prospective single-center study and received either risperidone (n=54) or olanzapine (n=59). They were followed prospectively for 12weeks. Average daily dose was 4.4mg/day for risperidone and 17.4mg/day for olanzapine. Plasma adiponectin levels as well as fasting metabolic parameters were measured at baseline, 6weeks and 12weeks. The two groups had similar baseline demographic and metabolic characteristics. A significant increase in body weight was observed over time. This increase was significantly larger in the olanzapine group than in the risperidone group (+7.0kg versus +3.1kg, p

OBJECTIVE To investigate 3-month changes in glucose metabolism in a naturalistic sample of patients with schizophrenia newly started on or switched to specific atypical antipsychotic medication therapy. METHOD One hundred eighty-three patients were evaluated before initiation and 3 months after with a 75-g glucose load oral glucose tolerance test (OGTT). Data were collected between November 2003 and January 2007. RESULTS Eight patients (4.4%) developed new-onset diabetes within 3 months. Initiation of clozapine resulted in a significantly higher risk for new-onset glucose abnormalities than initiation of aripiprazole (odds ratio = 67.29, 95% CI = 5.23 to 866.49). Significant drug x time interactions were found for all OGTT glucose assessments (fasting: F = 6.79, df = 5,177; p < .0001; 30 minutes: F = 3.89, df = 5,177; p = .0023; 60 minutes: F = 5.03, df = 5,177; p = .0002; 120 minutes: F = 3.78, df = 5,177; p = .0028), with the evolution of plasma glucose levels being significantly worse in patients initiated on clozapine therapy (fasting, 30 minutes, and 60 minutes), olanzapine therapy (fasting, 60 minutes, and 120 minutes), and quetiapine therapy (fasting and 60 minutes) than in patients initiated on aripiprazole therapy (p < .05). Clozapine was also significantly more deleterious than risperidone and amisulpride for fasting plasma glucose level changes (p < .05). Type of initiation (start or switch) did not affect any of the metabolic parameters. CONCLUSIONS The incidence of new-onset glucose abnormalities, including diabetes, in the first 3 months after newly starting or switching atypical antipsychotic medication is high and may be markedly influenced by type of prescribed antipsychotic. The importance of accurately screening for new-onset glucose abnormalities after initiation of an atypical antipsychotic is emphasized.

Background: In recent years, several studies showed increased rates of hyperglycaemia, diabetes, dyslipidemia, metabolic syndrome as well as cardiovascular disease in schizophrenic patients. The underlying mechanism, however, is poorly understood. Adiponectin is a recently identified adipocyte-derived protein, with low adiponectin levels being associated with metabolic abnormalities such as obesity, insulin resistance and type 2 diabetes. Methods: Fasting adiponectin levels were assessed in a cross-sectional sample of 386 patients with schizophrenia or schizoaffective disorder. All patients were on monotherapy of second-generation antipsychotics (SGA) and underwent an extensive metabolic screening including an oral glucose tolerance test (OGTT). Results: Adiponectin plasma levels were inversely correlated with BMI, and differed significantly between patients with normal weight, overweight or obesity (p

ObjectiveTo evaluate quality of life and patient preference for schizophrenia treatment in a community based study comparing the use of aripiprazole to the standard of care (SOC).MethodThis open-label, 26-week, multi-centre, randomised study compared aripiprazole with SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Preference of Medicine (POM) questionnaire, the Quality of Life Scale (QLS), and the EuroQoL-5D (EQ-5D). The results from these outcome research variables are the focus of this paper addressing quality of life and patient preference.ResultsA total of 555 patients were randomised to receive aripiprazole (n = 284) or SOC (n = 271). The OC data at Week 26, reported that more respondents rated the study medication as ‘much better’ compared with their previous medication in the aripiprazole group versus SOC for patients (59% vs 35%, P < 0.001) and caregivers (58% vs 30%, P = 0.014). The improvement in QLS total score was also significantly greater in the aripiprazole group compared with SOC – mean change from baseline in QLS total score of 16.21 vs 10.01 (P < 0.001) at Week 26 (OC data set). A greater proportion of patients (93% vs 85%; P = 0.005) in the aripiprazole group had a satisfactory response on the EQ-5D Self Care Scale; all other EQ-5D scores were similar.ConclusionThe study findings suggest that quality of life and patient medication preference measures were better for aripiprazole than for SOC.

The presence of the metabolic syndrome (MetS) is an important risk factor for cardiovascular disease and diabetes. There are limited data on the prevalence of MetS in patients with schizophrenia at the onset of the disorder and specifically no data on patients treated in the era when only first-generation antipsychotics were available. Methods Data from a historic cohort of consecutively admitted first-episode patients with schizophrenia treated with first-generation antipsychotics (FGAs) were compared with an age and sex matched series of consecutive first-episode patients treated only with second-generation antipsychotics (SGAs). Rates of MetS were compared at baseline and after on average 3 years of treatment exposure. Results At first episode there was no difference in the prevalence of MetS between the historic and the current cohort. Rates of MetS increased over time in both groups, but patients started on SGAs had a three times higher incidence rate of MetS (Odds Ratio 3.6, CI 1.7–7.5). The average increase in weight and body mass index was twice as high in patients started on SGA. The difference between the FGA and SGA group was no longer significant when patients started on clozapine and olanzapine were excluded. Conclusion Rates of MetS at the first episode of schizophrenia today are not different from those of patients 15 to 20 years ago. This finding counters the notion that the high rates of metabolic abnormalities in patients with schizophrenia currently reported are mainly due to lifestyle changes over time in the general population. Some SGAs have a significantly more negative impact on the incidence of MetS compared to FGAs in first-episode patients.

Mortality rates in patients with schizophrenia are double compared with the general population, with cardiovascular disease causing 50% of the excess. Lowering low-density lipoprotein cholesterol is recognized as a primary target for the prevention of cardiovascular mortality. The effects of lipid-lowering treatment were evaluated in patients with schizophrenia. Forty-six patients with schizophrenia and with severe dyslipidaemia were identified. All were treated with antipsychotics. Patients were screened for cardiovascular risk factors and examined at baseline when statin therapy was initiated. The effects of lipid-lowering medication on lipid profile, glucose homeostasis and components of metabolic syndrome were evaluated at 3 months follow-up. After 3 months of statin therapy, a significant decrease in triglycerides, total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and, in associated ratios, low-density lipoprotein/high-density lipoprotein, cholesterol/high-density lipoprotein was observed. No significant changes occurred in high-density lipoprotein cholesterol, body mass index, waist circumference or glucose homeostasis. The only component of metabolic syndrome affected by statin therapy has been the serum triglyceride level. Statins proved effective in the management of dyslipidaemia in patients with schizophrenia treated with antipsychotics. More complex treatment may be required for associated metabolic disturbances.

BackgroundNaturalistic effectiveness trials of atypical antipsychotics are needed to provide broader information on efficacy, safety, and tolerability in patients with schizophrenia treated in a community practice setting.Methodin this 26-week, open-label, multicentre study, patients with schizophrenia requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled were randomized to receive aripiprazole or an atypical antipsychotic standard of care (SOC) treatment (i.e., olanzapine, quetiapine, or risperidone based on the investigator's judgment of the optimal treatment for the individual patient and the patient's prior response to antipsychotic medication). The primary objective was to compare the effectiveness of a 26-week treatment of aripiprazole versus SOC, as measured by the investigator Assessment Questionnaire (IAQ) total score at Week 26 last observation carried forward (LOCF) (primary endpoint), a validated measure that monitors relief or worsening of 10 key symptoms associated with the psychopathology of schizophrenia and side effects of antipsychotic treatment. Secondary objectives were to further assess effectiveness using the Clinical Global Impression – Global Improvement (CGI-I) and Clinical Global Impression – Severity of Illness scale, to assess time to treatment discontinuation, patient preference of medication, quality of life, and the tolerability of aripiprazole compared with SOC.ResultsAripiprazole treatment (n = 268) resulted in significantly better effectiveness than SOC treatment (n = 254; P < 0.001; Week 26 LOCF) as evidenced by the IAQ total score beginning at Week 4 (the first assessment point) and sustained through Week 26. A similar relationship was demonstrated among patients who completed the study (observed cases analysis); aripiprazole was associated with significantly better effectiveness at all time points with a greater differential effect from SOC over time. Patients treated with aripiprazole also demonstrated significantly greater improvements on the CGI-I scale (responder rate, P = 0.009 at Week 26 LOCF), as well as on quality of life (Quality of Life scale total score; P < 0.001 at Week 26). Furthermore, a significantly higher proportion of patients receiving aripiprazole rated their study medication as “much better” on the Preference of Medication Questionnaire (POM) scale than their pre-study medication compared with SOC patients (P < 0.001; Week 26). Time to treatment discontinuation and rates of discontinuation due to adverse events were similar in both treatment groups. The incidence of patients with one or more extrapyramidal symptom (e.g., akathisia, dystonia, parkinsonian events, and residual events) was higher in patients receiving aripiprazole compared with patients treated with SOC (13.5% vs. 5.6%); however, a higher proportion of patients in the SOC-treated group had clinically significant weight gain (21.2% vs. 7.3% for aripiprazole) and potentially clinically relevant elevated fasting levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and serum prolactin compared with patients receiving aripiprazole.ConclusionsAripiprazole is an effective atypical antipsychotic for the treatment of schizophrenia, demonstrating better effectiveness than SOC agents used in this study in patients for whom a switch in antipsychotic medication was warranted.

Metabolic abnormalities occur frequently in patients treated with antipsychotics and are of growing concern to clinicians. This study sought to determine whether antipsychotic-associated metabolic abnormalities identified through intensive monitoring can be reversed by switching to aripiprazole. Recent evidence suggests that aripiprazole may exhibit a favorable metabolic safety profile. The study population is a subset of a large (n > 500) ongoing prospective cohort. Thirty-one consecutive patients with schizophrenia who were started on aripiprazole were included in the study. All patients underwent an extensive metabolic evaluation, including an oral glucose tolerance test, at baseline, at 6 weeks, and at 3 months post switch. Metabolic abnormalities were defined as any of the following: new onset diabetes, impaired fasting glucose, impaired glucose tolerance, metabolic syndrome (MetS) according to various definitions, and dyslipidemia. After 3 months of treatment with aripiprazole (mean daily dose 16.3 mg), there was a significant decrease in body weight, body mass index, and waist circumference. There was a significant reduction in fasting glucose, fasting insulin, insulin resistance index, and serum lipids levels (cholesterol, triglycerides, low-density lipoprotein (LDL), LDL/HDL, Chol/HDL, and non-HDL cholesterol). There was also a significant reduction in prolactin levels. All 7 cases of recent onset diabetes were reversed at 3 months follow-up. The MetS was reversed in 50% of patients at 3 months follow-up. Our results support the reversibility of recent onset diabetes on antipsychotic medication when detected early and followed by a switch to aripiprazole.

Generally, assessment of fasting glucose is recommended as screening and monitoring for diabetes (ADA/APA consensus, 2004) although an Oral Glucose Tolerance Test (OGTT) remains the gold standard (Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, 2003). HbA1c is accepted as a useful index of mean blood glucose levels in the treatment of patients with diabetes but was not selected by the expert committee as a means for screening (Expert committee on the Diagnosis and Classification of Diabetes Mellitus, 2003; Kilpatrick et al., 1998; Mulkerin et al., 1992; Rohlfmg et al., 2000).

At present, antipsychotic drugs are not specifically referred to in the list of substances that can induce diabetes in the most recent American Diabetes Association guidelines (1), but there is a growing body of evidence that antipsychotic drugs might have diabetogenic properties (2,3). At present, there are no clear guidelines on what the best therapeutic strategies are when diabetes is detected during treatment with antipsychotics. Data from pharmacovigilance studies suggest that a significant proportion of recent-onset cases of diabetes can be reversed. Recent Belgian guidelines for screening and monitoring patients treated with antipsychotics propose a switch to an antipsychotic with a safer metabolic profile, but this …

Introduction L’effet des antipsychotiques de seconde generation sur les concentrations plasmatiques d’adiponectine est mal connu. Cette etude ouverte prospective monocentrique compare les effets de l’olanzapine (OLA) et de la risperidone (RIS) sur les taux d’adiponectine et divers parametres metaboliques. Patients et Methodes 113 patients schizophrenes (65% hommes, 32,3 annees), naifs de tout traitement par antipsychotiques, ont recu soit de la RIS (n = 54 ; dose moyenne 4,35 mg/jour), soit de l’OLA (n = 59 ; dose moyenne 17,6 mg/ jour) et ete suivis 12 semaines avec mesure du poids, des parametres metaboliques a jeun (glucose, insuline, lipides) et des concentrations plasmatiques d’adiponectine. Resultats L’indice de masse corporelle (IMC : 23,7 vs 23,2 kg/m 2 ), la prevalence du syndrome metabolique (SM selon le NCEP-ATPIII : 7,4 vs 8,0%), la glycemie a jeun (86,8 vs 86,9 mg/dl), l’insulinemie (11,4 vs 12,0 mIU/ml) et les taux d’adiponectine (10 154 vs 11 280 ng/ml) sont comparables a l’inclusion dans les groupes RIS et OLA, respectivement. La prise de poids est plus importante sous OLA que sous RIS (apres 12 semaines : +7 kg vs +3,1 kg, p Discussion L’evolution differente des taux d’adiponectine suggere des effets specifiques des deux antipsychotiques sur le tissu adipeux, ce qui pourrait contribuer au risque metabolique plus marque en clinique de OLA par comparaison a RIS. Conclusion Lors de l’initiation d’un traitement par antipsychotiques de seconde generation chez des patients schizophrenes, l’olanzapine, contrairement a la risperidone, diminue les taux d’adiponectine et ce, independamment des variations de l’IMC.

Background The aim of this paper is to evaluate the effect of antipsychotics for the treatment of schizophrenia in a community based study on sexual function and prolactin levels comparing the use of aripiprazole and standard of care (SOC), which was a limited choice of three widely used and available antipsychotics (olanzapine, quetiapine or risperidone) (The Schizophrenia Trial of Aripiprazole [STAR] study [NCT00237913]). Method This open-label, 26-week, multi-centre, randomised study compared aripiprazole to SOC (olanzapine, quetiapine or risperidone) in patients with schizophrenia (DSM-IV-TR criteria). The primary effectiveness variable was the mean total score of the Investigator Assessment Questionnaire (IAQ) at Week 26. The outcome research variables included the Arizona Sexual Experience scale (ASEX). This along with the data collected on serum prolactin levels at week 4, 8, 12, 18 and 26 will be the focus of this paper. Results A total of 555 patients were randomised to receive aripiprazole (n = 284) or SOC (n = 271). Both treatment groups experienced improvements in sexual function from baseline ASEX assessments. However at 8 weeks the aripiprazole treatment group reported significantly greater improvement compared with the SOC group (p = 0.007; OC). Although baseline mean serum prolactin levels were similar in the two treatment groups (43.4 mg/dL in the aripiprazole group and 42.3 mg/dL in the SOC group, p = NS) at Week 26 OC, mean decreases in serum prolactin were 34.2 mg/dL in the aripiprazole group, compared with 13.3 mg/dL in the SOC group (p < 0.001). Conclusion The study findings suggest that aripiprazole has the potential to reduce sexual dysfunction, which in turn might improve patient compliance.

Background and Aim:To evaluate safety, tolerability and overall effectiveness of a titrated- versus fixed-dose switching strategy from risperidone to aripiprazole in a general practice setting.Methods:This 12-week, multicentre, open-label study included patients with schizophrenia (DSM-IV-TR) experiencing insufficient efficacy and/or safety/tolerability issues while receiving risperidone for ≥6 weeks. Patients were randomized to titrated- or fixed-dose switching regimens.Results:Discontinuations due to AEs were similar between titrated- and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Titrated- and fixed-dose groups showed improvements (Week 12) in mean PANSS Total scores (–14.8 vs. –17.2; LOCF), mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF), ASEX scores (–1.5 vs. –1.9 from baseline; OC), serum prolactin levels (−48.7 vs. −48.5 from baseline; OC) and SWN scores (+8.6 vs. +10.3 from baseline; p=0.223; OC). POM scores indicated a preference for aripiprazole compared with risperidone using either regimen. Both strategies showed improvements (titrated-dose vs. fixed-dose; Week 12; LOCF) in social cognition as indicated by decreased GEOPTE patient (–5.3 vs. –6.1), caregiver (–5.4 vs. –9.9) and index scores (–5.1 vs. –9.8).Conclusion:Switching to aripiprazole from risperidone can be effectively and safely achieved in a general practice setting through a slow down-titration of risperidone and either a titrated- or fixed-dose switching strategy for aripiprazole.

Purpose:To evaluate the efficacy and safety of aripiprazole monotherapy as acute and continuation therapy for acute bipolar I mania.Methods:Patients with acute bipolar I mania were randomized (1:1:1) to double-blind aripiprazole (15–30 mg/day; n=155), placebo (n=165) or lithium (900–1500 mg/day; n=160) for 3 weeks. At the end of Week 3, patients randomized to placebo were blindly switched to aripiprazole. Key efficacy outcome measures were mean change from baseline in YMRS Total score at Week 3 (LOCF; primary endpoint) and Week 12.Results:Improvements in YMRS Total scores from baseline were significantly greater versus placebo as early as Day 2 with aripiprazole (p=0.003) and Day 7 with lithium (p=0.040; LOCF). At Week 3, improvements from baseline in mean YMRS Total scores were significantly greater with aripiprazole (–12.96; p

Introduction Les troubles metaboliques sont frequents chez les patients psychiatriques, mais leur frequence en fonction du diagnostic psychiatrique est mal connue. Patients et methodes Tous les patients avec un diagnostic precis de troubles bipolaires (n = 112), schizophrenie (n = 503) et desordres schizoaffectifs (n = 92) ont ete evalues prospectivement a la recherche d’un syndrome metabolique (SM, criteres du NCEP-ATPIII 2004), d’un « pre-diabete » (« IFG/IGT » dans HGPO) ou d’un diabete. Une analyse de regression logistique a evalue si le diagnostic psychiatrique est un facteur independant de risque metabolique. Resultats SM est present chez 23,2 %, 28,8 % et 50,0 % des patients avec troubles bipolaires, schizophrenie et desordres schizoaffectifs, respectivement (p Discussion Les differences de risque metabolique persistent apres ajustement pour les nombreux facteurs confondants anthropometriques, relatifs au style de vie, a la duree/severite de la maladie ou aux divers medicaments, psychotropes ou non, ce qui suggere une composante genetique a confirmer. Conclusion Le diagnostic psychiatrique est un facteur de risque independant d’anomalies glycemiques et metaboliques, avec le risque maximum pour les desordres schizoaffectifs, intermediaire pour la schizophrenie et minimum pour les troubles bipolaires, meme apres ajustement pour les facteurs confondants.

Background and aims:The management of psychotic symptoms is critical to schizophrenia treatment. However, monitoring patients' physical health, in particular how this impacts life expectancy, quality of life and compliance, should be considered because of its significant influence on short and long term health outcomes.Methods:Between June and October 2006, 54,618 European psychiatrists in 12 countries received a survey containing 10 questions addressing physical health. Responders rated areas of concern, physical health monitoring and impact of antipsychotic therapy.Results:Among the first 3,764 psychiatrists, 84% consider physical health very important, with weight as the major concern for 63%. The top concerns in terms of impact of physical health are compliance (41%) followed by increased mortality risk (38%). While 88% say they undertake physical examination, only half do so on a regular basis. The most problematic side effects of antipsychotic treatments are weight gain (56%), metabolic impact (29%), extrapyramidal symptoms (21%) and sedation (7%), but only 1% report insomnia as an issue. When considering treatment related weight gain, 85% provide diet and lifestyle education with 55% monitoring weight, however, 66% of this intervention is unsuccessful.Conclusions:The results show a substantial interest and awareness in the management of physical health in schizophrenia. Psychiatrists are monitoring to a certain extent but management strategies are often unsuccessful. Effective physical health programs in schizophrenia, including close monitoring and weight management, have yet to be optimized across Europe.

Background and aims:To assess sociodemographic characteristics, including education, usual residence, employment status and income among schizophrenia patients in Europe.Methods:The Client Sociodemographic and Service Receipt Inventory was evaluated in schizophrenia patients treated with aripiprazole versus standard of care (SoC). 555 patients were equally randomized to aripiprazole (10-30 mg/day) or SoC (olanzapine 5-20 mg/day, or quetiapine 100-800 mg/day or risperidone 2-8 mg/day, [up to 16 mg/day]) for 26 weeks.Results:At baseline, 67% of the patients were single, 15% married and 12% widowed. The average years of education was 11.2: 24% of the patients received primary education or less, 50% secondary education; 21% further education and only 8% reached university. Of this population, 35% lived alone, 33% lived with relatives other than parents, and 14% lived with their husband/wife. More patients in the aripiprazole than the SoC group were employed (18.5% vs. 19. 9%), while a similar proportion were unemployed (28.8% vs. 25.8%). Among the patients who work (n=105), only two have a managerial position: 35% of patients are on a state pension. The main income source across all countries was state benefit and pension (74%). Only 15% of patients had an effective salary. During the 3 months prior to baseline, patients missed ~18.5 days (50%) from work due to illness.Conclusions:Despite improvements in the management of psychosis with second-generation antipsychotics, the social and rehabilitation aspects of schizophrenia warrant further attention.