A Method to Compare the Delivery of Psychiatric Care for People with Treatment-Resistant Schizophrenia

Abstract Introduction: Community services are gaining ground when it comes to attention to patients with psychiatric diseases. Regarding patients with treatment-resistant schizophrenia (TRS), the use of information and communication technology (ICT) could help to shift the focus from hospital-centered attention to community services. This study compares the differences in mental health services provided for patients with TRS in Budapest (Hungary), Tel-Aviv (Israel) and Catalonia (Spain) by means of a method for the quick appraisal of gaps among the three places, for a potential implementation of the same ICT tool in these regions. Methods: An adapted version of the Description and Standardised Evaluation of Services and Directories in Europe for Long Term Care (DESDE-LTC) instrument was made by researchers in Semmelweis University (Budapest, Hungary), Gertner Institute (Tel-Aviv, Israel) and Hospital de la Santa Creu I Sant Pau and Parc Sanitari Sant Joan de Déu (Catalonia, Spain). Results: Two types of outpatient care services were available in the three regions. Only one type of day-care facility was common in the whole study area. Two residential care services, one for acute and the other for non-acute patients were available in every region. Finally, two self-care and volunteer-care facilities were available in the three places. Conclusion: Although the availability of services was different in each region, most of the services provided were sufficiently similar to allow the implementation of the same ICT solution in the three places.The m-RESIST Group is composed of: Francisco Alcalde Enrico d’Amico Caritat Almazán Anna Alonso-Solís Jesús Berdún István Bitter Walter Baccinelli Chiara Bonizzi María Bulgheroni Johanna Caro Mendivelso Asaf Caspi Tanguy Coenen Anat Cohen Xavier Constant Iluminada Corripio Marisol Escobar Kinga Farkas Kata Fazekas Yoram Feldman Emmanuel Gimenez Shenja van der Graaf Eva Grasa Levente Herman Margarita Hospedales Elena Huerta-Ramos Matti Isohanni Erika Jääskeläinen Charlotte Jewel Teija Juola Timo Jämsä Rachelle Kaye Panagiotis Kokkinakis Hannu J. Koponen Silvia Marcó Gregoris Mentzas Jouko Miettunen Jani Moilanen Susana Ochoa Ilias Papas Fotis Paraskevopoulos Elisabeth Reixach Alexandra Roldán Katya Rubinstein Elena Rubio-Abadal Garifalia Sebú Annika Seppälä Jussi Seppälä Valentina Simonetti Matthias Stevens Vittorio Tauro Anna Triantafillou Zsolt Szabolcs Unoka Judith Usall Vincenzo Vella David Vermeir Ilaria de Vit

Negative symptoms and sex differences in first episode schizophrenia: What's their role in the functional outcome? A longitudinal study

Introduction: Negative symptoms (NS) include asociality, avolition, anhedonia, alogia, and blunted affect and are linked to poor prognosis. It has been suggested that they reflect two different factors: diminished expression (EXP) (blunted affect and alogia) and amotivation/pleasure (MAP) (anhedonia, avolition, asociality). The aim of this article was to examine potential sex differences among first-episode schizophrenia (FES) patients and analyze sex-related predictors of two NS symptoms factors (EXP and MAP) and functional outcome. Material and methods: Two hundred and twenty-three FES (71 females and 152 males) were included and evaluated at baseline, six-months and one-year. Repeated measures ANOVA was used to examine the effects of time and sex on NS and a multiple linear regression backward elimination was performed to predict NS factors (MAP-EXP) and functioning. Results: Females showed fewer NS (p = 0.031; Cohen's d = −0.312), especially those related to EXP (p = 0.024; Cohen's d = −0.326) rather than MAP (p = 0.086), than males. In both male and female group, worse premorbid adjustment and higher depressive symptoms made a significant contribution to the presence of higher deficits in EXP at one-year follow-up, while positive and depressive symptoms predicted alterations in MAP. Finally, in females, lower deficits in MAP and better premorbid adjustment predicted better functioning at one-year follow-up (R2 = 0.494; p < 0.001), while only higher deficits in MAP predicted worse functioning in males (R2 = 0.088; p = 0.012). Conclusions: Slightly sex differences have been found in this study. Our results lead us to consider that early interventions of NS, especially those focusing on motivation and pleasure symptoms, could improve functional outcomes

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019 : A systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Measuring universal health coverage based on an index of effective coverage of health services in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Achieving universal health coverage (UHC) involves all people receiving the health services they need, of high quality, without experiencing financial hardship. Making progress towards UHC is a policy priority for both countries and global institutions, as highlighted by the agenda of the UN Sustainable Development Goals (SDGs) and WHO's Thirteenth General Programme of Work (GPW13). Measuring effective coverage at the health-system level is important for understanding whether health services are aligned with countries' health profiles and are of sufficient quality to produce health gains for populations of all ages. Methods Based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we assessed UHC effective coverage for 204 countries and territories from 1990 to 2019. Drawing from a measurement framework developed through WHO's GPW13 consultation, we mapped 23 effective coverage indicators to a matrix representing health service types (eg, promotion, prevention, and treatment) and five population-age groups spanning from reproductive and newborn to older adults (≥65 years). Effective coverage indicators were based on intervention coverage or outcome-based measures such as mortality-to-incidence ratios to approximate access to quality care; outcome-based measures were transformed to values on a scale of 0–100 based on the 2·5th and 97·5th percentile of location-year values. We constructed the UHC effective coverage index by weighting each effective coverage indicator relative to its associated potential health gains, as measured by disability-adjusted life-years for each location-year and population-age group. For three tests of validity (content, known-groups, and convergent), UHC effective coverage index performance was generally better than that of other UHC service coverage indices from WHO (ie, the current metric for SDG indicator 3.8.1 on UHC service coverage), the World Bank, and GBD 2017. We quantified frontiers of UHC effective coverage performance on the basis of pooled health spending per capita, representing UHC effective coverage index levels achieved in 2019 relative to country-level government health spending, prepaid private expenditures, and development assistance for health. To assess current trajectories towards the GPW13 UHC billion target—1 billion more people benefiting from UHC by 2023—we estimated additional population equivalents with UHC effective coverage from 2018 to 2023. Findings Globally, performance on the UHC effective coverage index improved from 45·8 (95% uncertainty interval 44·2–47·5) in 1990 to 60·3 (58·7–61·9) in 2019, yet country-level UHC effective coverage in 2019 still spanned from 95 or higher in Japan and Iceland to lower than 25 in Somalia and the Central African Republic. Since 2010, sub-Saharan Africa showed accelerated gains on the UHC effective coverage index (at an average increase of 2·6% [1·9–3·3] per year up to 2019); by contrast, most other GBD super-regions had slowed rates of progress in 2010–2019 relative to 1990–2010. Many countries showed lagging performance on effective coverage indicators for non-communicable diseases relative to those for communicable diseases and maternal and child health, despite non-communicable diseases accounting for a greater proportion of potential health gains in 2019, suggesting that many health systems are not keeping pace with the rising non-communicable disease burden and associated population health needs. In 2019, the UHC effective coverage index was associated with pooled health spending per capita (r=0·79), although countries across the development spectrum had much lower UHC effective coverage than is potentially achievable relative to their health spending. Under maximum efficiency of translating health spending into UHC effective coverage performance, countries would need to reach $1398 pooled health spending per capita (US$ adjusted for purchasing power parity) in order to achieve 80 on the UHC effective coverage index. From 2018 to 2023, an estimated 388·9 million (358·6–421·3) more population equivalents would have UHC effective coverage, falling well short of the GPW13 target of 1 billion more people benefiting from UHC during this time. Current projections point to an estimated 3·1 billion (3·0–3·2) population equivalents still lacking UHC effective coverage in 2023, with nearly a third (968·1 million [903·5–1040·3]) residing in south Asia. Interpretation The present study demonstrates the utility of measuring effective coverage and its role in supporting improved health outcomes for all people—the ultimate goal of UHC and its achievement. Global ambitions to accelerate progress on UHC service coverage are increasingly unlikely unless concerted action on non-communicable diseases occurs and countries can better translate health spending into improved performance. Focusing on effective coverage and accounting for the world's evolving health needs lays the groundwork for better understanding how close—or how far—all populations are in benefiting from UHC

Alteraciones en la conectividad funcional de la “Default mode Network” en pacientes con psicosis: estudio de neuroimagen funcional en estado de reposo

En los últimos años, el descubrimiento de la existencia de redes neuronales que muestran coherencia en cuanto a su actividad espontánea durante el reposo, fenómeno conocido con el nombre de conectividad funcional (CF), ha proporcionado un medio fructífero para abordar las bases neurobiológicas de enfermedades psiquiátricas como la esquizofrenia. Uno de los muchos sistemas cerebrales que muestran patrones de actividad sincronizada es la “Default mode Network” (DN), red formada por una serie de regiones que disminuyen su actividad simultáneamente durante la realización de tareas cognitivas y que se activan durante periodos libres de tarea. Numerosos estudios han observado alteraciones en esta red en pacientes con esquizofrenia, sin embargo, existen una serie de factores limitantes para la interpretación y generalización de estos resultados: la mayoría de estos trabajos se han realizado con pacientes crónicos, sin fenotipos definidos y en diferentes estadios de la enfermedad. Por ello, en un intento de elucidar parámetros biológicos que definan fenotipos consistentes, los objetivos de estas tesis son, por un lado, estudiar la CF de la DN en las primeras fases de la enfermedad psicótica, y por otro lado, estudiar la CF de la DN en dos grupos de pacientes con esquizofrenia clínicamente diferenciados (uno con alucinaciones auditivas (AA) persistentes y otro sin historia de AA). Para ello, en el primero de los trabajos, se realizan adquisiciones de resonancia magnética funcional en estado de reposo (R-fMRI) en una muestra de 19 pacientes con un primer episodio de psicosis y 19 controles sanos. Posteriormente, se examina la CF de 11 semillas previamente seleccionadas pertenecientes a los dos subsistemas que conforman la DN (córtex dorsomedial prefrontal y lóbulo temporal medial), según trabajos previos de Andrews- Hanna. En el segundo trabajo se realizan adquisiciones de R-fMRI en una muestra de 19 pacientes con esquizofrenia y AA persistentes, 14 pacientes con esquizofrenia sin historia de AA y 20 controles sanos. Siguiendo la misma metodología que en el estudio anterior, se examina la CF de los dos subsistemas que conforman la DN. Los resultados muestran que la CF de la DN estaría ya alterada desde el inicio de la enfermedad psicótica. Además, en el caso de los pacientes con un primer episodio de psicosis, éstas alteraciones parecen limitarse al subsitema del córtex dorsomedial prefrontal. Los pacientes con esquizofrenia en cambio, aunque muestran alteraciones en ambos subsistemas de la DN, éstas són mucho mayores en el caso de los pacientes alucinadores, llegando a afectar a todas y cada una de las semillas examinadas. Además, los resultados muestran un patrón de alteraciones en la CF entre regiones pertenecientes a ambos subsystemas de la DN y regiones clave de la “Salience Network”, entre otras áreas, característico de los pacientes alucinadores.In recent years, the discovery of the existence of neural networks that show consistency in their spontaneous activity at rest, a phenomenon known as functional connectivity (FC), has provided a fruitful means of addressing the neurobiological basis of psychiatric diseases such as schizophrenia. One of several brain systems showing patterns of synchronized activity is the "Default mode Network" (DN), a network comprised of a number of regions that decrease their activity simultaneously when performing cognitive tasks and increase their activity during free task periods. Numerous studies have found abnormalities in this network in patients with schizophrenia. However, there are some limitations for the interpretation and generalization of these results; most of these studies were performed with chronic patients, without defined phenotypes and at different stages of the disease. Therefore, in an attempt to elucidate biological parameters that define consistent phenotypes, the objectives of this thesis are: firstly, to study the DN FC in the early stages of psychotic illness, and secondly, to study the DN FC in two clinically differentiated groups of patients with schizophrenia (one with persistent auditory hallucinations (AH) and one without a history of AH). To do so, in the first study, resting state functional magnetic resonance imaging acquisitions (R-fMRI) were performed on a sample of 19 patients with a first episode of psychosis and 19 healthy controls. Subsequently, taking advantage of the fractionation of the DN into two distinct subsystems (dorsomedial prefrontal cortex subsystem, and medial temporal lobe subsystem) and a validated set of 11 seed regions-of-interest (Andrews – Hanna), we examined the FC in all eleven of them. In the second study, R-fMRI acquisitions were performed on a sample of 19 patients with schizophrenia and persistent AH, 14 schizophrenia patients without a history of AH and 20 healthy controls. Following the same methodology as in the previous study, we examined the FC of the 11 ROI comprised in the DN. The results show that the DN FC is altered from the begining of psychotic illness. Furthermore, in the case of patients with a first episode of psychosis, these abnormalities appear to be limited to the dorsomedial prefrontal cortex subsystem. In the second study, both groups of patients exhibited alterations in both dMPFC and MTL subsystems of the DN. However, these alterations were greater in patients with persistent AH. In particular, these patients exhibited cross-network abnormalities between the DN and the salience processing system

Alteraciones en la conectividad funcional de la “Default mode Network” en pacientes con psicosis: estudio de neuroimagen funcional en estado de reposo

En los últimos años, el descubrimiento de la existencia de redes neuronales que muestran coherencia en cuanto a su actividad espontánea durante el reposo, fenómeno conocido con el nombre de conectividad funcional (CF), ha proporcionado un medio fructífero para abordar las bases neurobiológicas de enfermedades psiquiátricas como la esquizofrenia. Uno de los muchos sistemas cerebrales que muestran patrones de actividad sincronizada es la “Default mode Network” (DN), red formada por una serie de regiones que disminuyen su actividad simultáneamente durante la realización de tareas cognitivas y que se activan durante periodos libres de tarea. Numerosos estudios han observado alteraciones en esta red en pacientes con esquizofrenia, sin embargo, existen una serie de factores limitantes para la interpretación y generalización de estos resultados: la mayoría de estos trabajos se han realizado con pacientes crónicos, sin fenotipos definidos y en diferentes estadios de la enfermedad. Por ello, en un intento de elucidar parámetros biológicos que definan fenotipos consistentes, los objetivos de estas tesis son, por un lado, estudiar la CF de la DN en las primeras fases de la enfermedad psicótica, y por otro lado, estudiar la CF de la DN en dos grupos de pacientes con esquizofrenia clínicamente diferenciados (uno con alucinaciones auditivas (AA) persistentes y otro sin historia de AA). Para ello, en el primero de los trabajos, se realizan adquisiciones de resonancia magnética funcional en estado de reposo (R-fMRI) en una muestra de 19 pacientes con un primer episodio de psicosis y 19 controles sanos. Posteriormente, se examina la CF de 11 semillas previamente seleccionadas pertenecientes a los dos subsistemas que conforman la DN (córtex dorsomedial prefrontal y lóbulo temporal medial), según trabajos previos de Andrews- Hanna. En el segundo trabajo se realizan adquisiciones de R-fMRI en una muestra de 19 pacientes con esquizofrenia y AA persistentes, 14 pacientes con esquizofrenia sin historia de AA y 20 controles sanos. Siguiendo la misma metodología que en el estudio anterior, se examina la CF de los dos subsistemas que conforman la DN. Los resultados muestran que la CF de la DN estaría ya alterada desde el inicio de la enfermedad psicótica. Además, en el caso de los pacientes con un primer episodio de psicosis, éstas alteraciones parecen limitarse al subsitema del córtex dorsomedial prefrontal. Los pacientes con esquizofrenia en cambio, aunque muestran alteraciones en ambos subsistemas de la DN, éstas són mucho mayores en el caso de los pacientes alucinadores, llegando a afectar a todas y cada una de las semillas examinadas. Además, los resultados muestran un patrón de alteraciones en la CF entre regiones pertenecientes a ambos subsystemas de la DN y regiones clave de la “Salience Network”, entre otras áreas, característico de los pacientes alucinadores.In recent years, the discovery of the existence of neural networks that show consistency in their spontaneous activity at rest, a phenomenon known as functional connectivity (FC), has provided a fruitful means of addressing the neurobiological basis of psychiatric diseases such as schizophrenia. One of several brain systems showing patterns of synchronized activity is the "Default mode Network" (DN), a network comprised of a number of regions that decrease their activity simultaneously when performing cognitive tasks and increase their activity during free task periods. Numerous studies have found abnormalities in this network in patients with schizophrenia. However, there are some limitations for the interpretation and generalization of these results; most of these studies were performed with chronic patients, without defined phenotypes and at different stages of the disease. Therefore, in an attempt to elucidate biological parameters that define consistent phenotypes, the objectives of this thesis are: firstly, to study the DN FC in the early stages of psychotic illness, and secondly, to study the DN FC in two clinically differentiated groups of patients with schizophrenia (one with persistent auditory hallucinations (AH) and one without a history of AH). To do so, in the first study, resting state functional magnetic resonance imaging acquisitions (R-fMRI) were performed on a sample of 19 patients with a first episode of psychosis and 19 healthy controls. Subsequently, taking advantage of the fractionation of the DN into two distinct subsystems (dorsomedial prefrontal cortex subsystem, and medial temporal lobe subsystem) and a validated set of 11 seed regions-of-interest (Andrews – Hanna), we examined the FC in all eleven of them. In the second study, R-fMRI acquisitions were performed on a sample of 19 patients with schizophrenia and persistent AH, 14 schizophrenia patients without a history of AH and 20 healthy controls. Following the same methodology as in the previous study, we examined the FC of the 11 ROI comprised in the DN. The results show that the DN FC is altered from the begining of psychotic illness. Furthermore, in the case of patients with a first episode of psychosis, these abnormalities appear to be limited to the dorsomedial prefrontal cortex subsystem. In the second study, both groups of patients exhibited alterations in both dMPFC and MTL subsystems of the DN. However, these alterations were greater in patients with persistent AH. In particular, these patients exhibited cross-network abnormalities between the DN and the salience processing system

Alteraciones en la conectividad funcional de la "Default mode Network" en pacientes con psicosis: estudio de neuroimagen funcional en estado de reposo

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018En los últimos años, el descubrimiento de la existencia de redes neuronales que muestran coherencia en cuanto a su actividad espontánea durante el reposo, fenómeno conocido con el nombre de conectividad funcional (CF), ha proporcionado un medio fructífero para abordar las bases neurobiológicas de enfermedades psiquiátricas como la esquizofrenia. Uno de los muchos sistemas cerebrales que muestran patrones de actividad sincronizada es la "Default mode Network" (DN), red formada por una serie de regiones que disminuyen su actividad simultáneamente durante la realización de tareas cognitivas y que se activan durante periodos libres de tarea. Numerosos estudios han observado alteraciones en esta red en pacientes con esquizofrenia, sin embargo, existen una serie de factores limitantes para la interpretación y generalización de estos resultados: la mayoría de estos trabajos se han realizado con pacientes crónicos, sin fenotipos definidos y en diferentes estadios de la enfermedad. Por ello, en un intento de elucidar parámetros biológicos que definan fenotipos consistentes, los objetivos de estas tesis son, por un lado, estudiar la CF de la DN en las primeras fases de la enfermedad psicótica, y por otro lado, estudiar la CF de la DN en dos grupos de pacientes con esquizofrenia clínicamente diferenciados (uno con alucinaciones auditivas (16) persistentes y otro sin historia de 16). Para ello, en el primero de los trabajos, se realizan adquisiciones de resonancia magnética funcional en estado de reposo (R-fMRI) en una muestra de 19 pacientes con un primer episodio de psicosis y 19 controles sanos. Posteriormente, se examina la CF de 11 semillas previamente seleccionadas pertenecientes a los dos subsistemas que conforman la DN (córtex dorsomedial prefrontal y lóbulo temporal medial), según trabajos previos de Andrews- Hanna. En el segundo trabajo se realizan adquisiciones de R-fMRI en una muestra de 19 pacientes con esquizofrenia y 16 persistentes, 14 pacientes con esquizofrenia sin historia de 16 y 20 controles sanos. Siguiendo la misma metodología que en el estudio anterior, se examina la CF de los dos subsistemas que conforman la DN. Los resultados muestran que la CF de la DN estaría ya alterada desde el inicio de la enfermedad psicótica. Además, en el caso de los pacientes con un primer episodio de psicosis, éstas alteraciones parecen limitarse al subsitema del córtex dorsomedial prefrontal. Los pacientes con esquizofrenia en cambio, aunque muestran alteraciones en ambos subsistemas de la DN, éstas són mucho mayores en el caso de los pacientes alucinadores, llegando a afectar a todas y cada una de las semillas examinadas. Además, los resultados muestran un patrón de alteraciones en la CF entre regiones pertenecientes a ambos subsystemas de la DN y regiones clave de la "Salience Network", entre otras áreas, característico de los pacientes alucinadores.In recent years, the discovery of the existence of neural networks that show consistency in their spontaneous activity at rest, a phenomenon known as functional connectivity (FC), has provided a fruitful means of addressing the neurobiological basis of psychiatric diseases such as schizophrenia. One of several brain systems showing patterns of synchronized activity is the "Default mode Network" (DN), a network comprised of a number of regions that decrease their activity simultaneously when performing cognitive tasks and increase their activity during free task periods. Numerous studies have found abnormalities in this network in patients with schizophrenia. However, there are some limitations for the interpretation and generalization of these results; most of these studies were performed with chronic patients, without defined phenotypes and at different stages of the disease. Therefore, in an attempt to elucidate biological parameters that define consistent phenotypes, the objectives of this thesis are: firstly, to study the DN FC in the early stages of psychotic illness, and secondly, to study the DN FC in two clinically differentiated groups of patients with schizophrenia (one with persistent auditory hallucinations (AH) and one without a history of AH). To do so, in the first study, resting state functional magnetic resonance imaging acquisitions (R-fMRI) were performed on a sample of 19 patients with a first episode of psychosis and 19 healthy controls. Subsequently, taking advantage of the fractionation of the DN into two distinct subsystems (dorsomedial prefrontal cortex subsystem, and medial temporal lobe subsystem) and a validated set of 11 seed regions-of-interest (Andrews - Hanna), we examined the FC in all eleven of them. In the second study, R-fMRI acquisitions were performed on a sample of 19 patients with schizophrenia and persistent AH, 14 schizophrenia patients without a history of AH and 20 healthy controls. Following the same methodology as in the previous study, we examined the FC of the 11 ROI comprised in the DN. The results show that the DN FC is altered from the begining of psychotic illness. Furthermore, in the case of patients with a first episode of psychosis, these abnormalities appear to be limited to the dorsomedial prefrontal cortex subsystem. In the second study, both groups of patients exhibited alterations in both dMPFC and MTL subsystems of the DN. However, these alterations were greater in patients with persistent AH. In particular, these patients exhibited cross-network abnormalities between the DN and the salience processing system

A Pharmacovigilance Study in First Episode of Psychosis : Psychopharmacological Interventions and Safety Profiles in the PEPs Project

The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines