Résumé en français Objectifs : Ce mémoire propose d’explorer l’assiduité aux interventions psychosociales chez les personnes atteintes de troubles psychotiques en répondant à trois questions : 1- Quels sont les facteurs influençant l’assiduité aux interventions psychosociales pour une clientèle atteinte de troubles psychotiques? 2- Sont-ils comparables aux facteurs influençant l’observance à la médication? 3- Quel est le taux d’abandon des interventions psychosociales et quels sont les facteurs qui font varier ce taux? Méthodes : Cette étude a permis de faire la synthèse des facteurs influençant l’observance à la médication à partir des revues systématiques publiées sur le sujet, et d’établir les facteurs influençant l’assiduité aux interventions psychosociales à partir des raisons d’abandon citées dans les essais cliniques randomisés publiés. Une méta-analyse a permis de combiner les essais cliniques rapportant les abandons et ainsi d’en établir un taux. Résultats : Nous avons répertorié 92 essais cliniques randomisés sur les interventions psychosociales avec les personnes atteintes de troubles psychotiques. De ce nombre, 43 ont permis de répertorier les raisons d’abandon. Les raisons d’abandon s’avèrent principalement liées à la maladie et liées à l’accessibilité, la continuité et la qualité des soins et services. Un taux d’abandon de 13% a été obtenu à partir de l’agrégation de 74 études dans la méta-analyse. Des facteurs faisant varier ce taux ont été identifiés. Conclusion : Plusieurs facteurs (personnels, lié aux traitements, sociaux) influençant l’assiduité aux interventions psychosociales chez les personnes atteintes de troubles psychotiques ont été identifiés. De plus, le faible taux d’abandon obtenu démontre bien la faisabilité clinique de ce type d’intervention. S’ajoutant à l’efficacité déjà bien démontrée de certaines modalités d’intervention psychosociales, le taux d’assiduité à ces mêmes modalités constitue un argument supplémentaire pour en assurer la disponibilité aux personnes atteintes d’un trouble psychotique. / Abstract Aims : This report suggest investigating the compliance in the psychosocial treatment among persons with schizophrenia spectrum disorder by answering three questions : 1- What are factors influencing compliance in the psychosocial treatment among persons with schizophrenia spectrum disorder? 2- Are they comparable to factors influencing compliance with pharmacological treatment? 3- What is the dropout rate of the psychosocial treatment and which are the factors which make vary this rate? Methods : A systematic review allowed to make the synthesis of factors influencing the compliance in the medication from the systematic reviews published on the subject and to establish factors influencing the compliance in the psychosocial treatment from the reasons of drop-out specified in the published randomized clinical trials. A meta-analysis allowed to combine clinical trials reporting drop-out and so to establish a rate. Results : We listed 92 clinical trials randomized on the psychosocial treatment among persons suffering from schizophrenia spectrum disorder , of this number 43 allowed to list the reasons of drop-out. The reasons of drop-out turn out mainly related to the disease and related to the accessibility, the continuity and the quality of the care and the services. A 13 % dropout rate was obtained from the aggregation of 74 studies in the meta-analysis. Factors making vary this rate were identified. Conclusions: Several factors which influence the compliance in the psychosocial treatment among persons suffering from schizophrenia spectrum disorders are identified. Furthermore, the low drop-out rate calculated demonstrates well the clinical feasibility of this type of treatment. Being added to the efficiency already well demonstrated by certain psychosocial modalities of treatnebt, the compliance rate in these same modalities establishes an additional argument to assure the availability among persons suffering from schizophrenia spectrum disorders.

Alterations in self-experience is a relatively omitted topic in czech literature. For that reason, the following diploma thesis deals with this issue, in relation to unipolar depression and schizophrenia spectrum disorders. The thesis is divided into two parts - theoretical and practical part of the research. Each chapter of the theoretical part summarizes the crucial information about schizophrenia and other disorders from schizophrenia spectrum that later appears in the research sample - as well as depression. The chapter describes symptomatology, diagnostics, epidemiology, etiopathogenesis and the treatment of the abovementioned disorders. Hereafter, the subject of alterations in self-experience is introduced and the two main phenomenologically oriented approaches to this phenomena. After that, the concrete manifestations of alterations in self-experience in schizophrenic disorders and depression are outlined. The concluding chapter of the theoretical part provides a brief account of the most famous methods in the research that focuses on alterations in self-experience. The research part of the thesis includes two sections. The first one aims to compare the changes in the experience of self in schizophrenic disorders and depression. For this purpose, the newly developed Self-disturbances Scale....

Background and objectives: Whilst Active and Receptive Music Therapy techniques have been widely researched and are employed within a range of contexts and with diverse client populations, this study reports on their specific qualitative musical and verbal affordances in major depressive disorder and schizophrenia-spectrum psychotic disorders. The study also describes and compares the respective and joint contributions of the music therapy techniques in giving rise to the affordances as well as reporting on the similarities and differences within and between diagnostic groups. This is the first study of its kind within the South African context. Methods: A qualitative research approach using a case study design, sampled purposefully twenty patients of the above mentioned diagnostic groups for participation in this study comprising a course of eight twice weekly music therapy sessions. The primary data sources were transcribed video recordings of therapy sessions and an individual in-depth semi-structured interview after the course of therapy. Clinical session notes served as a corroborative data source. In-depth content and thematic analysis explored and compared qualitative affordances during music therapy comprising active and Receptive Music Therapy techniques. The qualitative affordances under investigation were i) musical qualities, and ii) verbal expressions. Emerging from these affordances were the respective and combined affordances of the music therapy techniques as well as the similarities and differences between the diagnostic groups. Findings: Thirteen themes emerged from the analysis of clients' verbatim verbal responses to both active music making and Receptive Music Therapy techniques. These themes are: i) not to feel; ii) to do or not to do; iii) grappling with the desired future; iv) hurt and fear of undesirable outcomes; v) sadness, brokenness and futility; vi) anger, trust and vulnerability; vii) desire for connection with and affection of others; viii) barricaded from being present, now; ix) tensing and un-tensing; x) personal relating to one’s musical expression; xi) reflections on the music and music making in therapy; xii) resilience and courage and xiii) invigoration and liberation. The Active Music Therapy techniques comprising clinical improvisation, structured musical exercises, drumming, vocal work, songwriting and movement, gave rise to ten themes expressing the musical affordances. The themes that emerged were i) reciprocal responding; ii) the explicit use of symbols through music; iii) regularity; iv) disturbance and difficulty; v) turning points; vi) energy bursting or lacking; vii) bodily synchrony; viii) intensified emotional expression; ix) exploring new territory and Active Music Therapy techniques comprising clinical improvisation, structured musical exercises, drumming, vocal work, songwriting and movement, gave rise to ten themes expressing the musical affordances. The themes that emerged were i) reciprocal responding; ii) the explicit use of symbols through music; iii) regularity; iv) disturbance and difficulty; v) turning points; vi) energy bursting or lacking; vii) bodily synchrony; viii) intensified emotional expression; ix) exploring new territory and x) resolution and arrival. The emerging themes express the extent of musical and verbal expression of all clients representing both diagnostic groups. Most saliently among clients with depression the affordances were the themes on accessing creativity, accessing and articulating internal feelings, experiencing resilient parts of self, reflecting on and integrating symbolic material, motivation to act and extending musical and verbal expression during social interaction. Among clients suffering from schizophrenia spectrum disorder, the most striking affordances were experiences of regularity and flow within disorganization, orientation to ‘here and now’ experiences through active music making and working with symbolic material expressed on a continuum of concrete to abstract. Clients from both diagnostic groups experienced a reduction in unwanted symptoms as expressed through increased energy levels, experiences of pleasure in music making and spontaneous musical and verbal self-expression. Conclusion: This study revealed qualitative affordances of specific music therapy techniques expressed through verbal content and musical qualities. These showed responses within a therapeutic relationship that express inter- and intra-personal connection, give voice to what is not always verbally accessible and facilitate multi-sensory, creative experiences, increased motivation, emotional expression, and the reclamation of energy, spontaneity and resilience. / Thesis (PhD)--University of Pretoria, 2017. / Psychiatry / PhD / Unrestricted

O presente estudo investigou a prevalência e a validade de construto das experiências psicóticas (EPs) na gestação e os fatores de risco associados em uma amostra comunitária do município de São Paulo. Foram investigados fatores de risco sociodemográficos, ambientais, transtornos psiquiátricos no presente e ao longo da vida, violência doméstica, capacidade intelectual e histórico familiar de transtornos psiquiátricos. Foram também avaliados desfechos da gestação e do parto. Trata-se de um estudo prospectivo, com início no 3º trimestre de gestação. As entrevistas de avaliação foram realizadas por psicólogos treinados. Para a avaliação das EPs, foi utilizado o instrumento de entrevista diagnóstica padronizada breve - Mini International Neuropsyquiatric Interview (M.I.N.I), validado para a realidade brasileira. Para os fatores de risco sociodemográficos, foram aplicados: questionário socioeconômico (QSE), densidade demográfica (DM) e utilizado o critério de classificação econômica do Brasil CCEB, pela Associação Brasileira de Empresas de Pesquisa (ABEP) e World Health Organization - WHO para violência doméstica. Foi realizada a avaliação da capacidade intelectual através da Escala de Inteligência Wechsler para adultos, terceira versão (WAISS-III) e investigado o histórico familiar para transtornos mentais através do The Family History Screen (FHS). Os resultados apontaram uma prevalência de 19,22% das EPs na gestação e compartilhando os fatores de risco presentes na esquizofrenia, como: urbanicidade, gestantes jovens, o uso de drogas e álcool, desvantagem socioeconômica, baixo nível de escolaridade, exposição à situações de violência, a presença dos transtornos psiquiátricos como depressão e ansiedade, e histórico familiar para qualquer condição psiquiátrica. Este estudo, realizado em uma região urbana da cidade de São Paulo, com altos índices de vulnerabilidade social, indica que a prevalência de EPs em gestantes é alta, afetando cerca de 1 em 6 mulheres. A presença de EPs associa-se fortemente com psicopatologia geral e com amplos fatores de risco. Neste sentido, a presença de EPs pode se constituir em um importante indicador de risco a ser avaliado em ambientes clínicos durante a gestação. Estudos futuros que possam investigar a sua utilidade para indicação de intervenções são necessários, assim como estudos que investiguem o curso de EPs apos o período gestacional e a sua associação com desfechos de saúde nas mulheres e em seus filhos / This research investigated the prevalence and construct validity of psychotic experiences (PEs) during pregnancy and the risk factors in a community sample in the city of São Paulo. Sociodemographic and environmental risk factors, psychiatric disorders, domestic violence, intellectual capacity and family history of psychiatric disorders in the present and throughout life were the investigated elements. Pregnancy and delivery outcomes were also evaluated. This is a prospective research, starting in the 3rd trimester of pregnancy. The evaluation interviews were conducted by trained psychologists. For the evaluation of PEs, the brief standardized diagnostic interview tool was used - Mini International Neuropsyquiatric Interview (M.I.N.I), validated for the Brazilian reality. For the sociodemographic risk factors, both socioeconomic questionnaire (SEQ) and population density (PD) were applied and the criterion of economic classification in Brazil (CECB) was used by the Brazilian Association of Research Companies (BARC) and World Health Organization - WHO for domestic violence. The intellectual capacity evaluation was carried out, using the Wechsler Intelligence Scale for Adults, third version (Waiss-III), and the family history of mental disorders was investigated through The Family History Screen (FHS). The results indicated a prevalence of 19.22% of PEs during pregnancy and sharing the risk factors present in schizophrenia, such as urbanicity, young pregnant women, use of drugs and alcohol, socioeconomically disadvantaged, low educational level, exposure to situations of violence, the presence of psychiatric disorders such as depression and anxiety, and family history of any psychiatric condition. This research, conducted in an urban area of the city of São Paulo, with high social vulnerability, indicates that the prevalence of PEs in pregnant women is high, affecting about 1 in 6 of them. The presence of PEs is strongly associated with general psychopathology and broad risk factors. In this sense, the presence of PEs may constitute an important risk factor to be evaluated in clinical environments during pregnancy. Future researches intending to look into its usefulness for indication of interventions are needed, as well as studies to search into the course of PEs after pregnancy and its association with health outcomes for women and their children

O presente estudo investigou a prevalência e a validade de construto das experiências psicóticas (EPs) na gestação e os fatores de risco associados em uma amostra comunitária do município de São Paulo. Foram investigados fatores de risco sociodemográficos, ambientais, transtornos psiquiátricos no presente e ao longo da vida, violência doméstica, capacidade intelectual e histórico familiar de transtornos psiquiátricos. Foram também avaliados desfechos da gestação e do parto. Trata-se de um estudo prospectivo, com início no 3º trimestre de gestação. As entrevistas de avaliação foram realizadas por psicólogos treinados. Para a avaliação das EPs, foi utilizado o instrumento de entrevista diagnóstica padronizada breve - Mini International Neuropsyquiatric Interview (M.I.N.I), validado para a realidade brasileira. Para os fatores de risco sociodemográficos, foram aplicados: questionário socioeconômico (QSE), densidade demográfica (DM) e utilizado o critério de classificação econômica do Brasil CCEB, pela Associação Brasileira de Empresas de Pesquisa (ABEP) e World Health Organization - WHO para violência doméstica. Foi realizada a avaliação da capacidade intelectual através da Escala de Inteligência Wechsler para adultos, terceira versão (WAISS-III) e investigado o histórico familiar para transtornos mentais através do The Family History Screen (FHS). Os resultados apontaram uma prevalência de 19,22% das EPs na gestação e compartilhando os fatores de risco presentes na esquizofrenia, como: urbanicidade, gestantes jovens, o uso de drogas e álcool, desvantagem socioeconômica, baixo nível de escolaridade, exposição à situações de violência, a presença dos transtornos psiquiátricos como depressão e ansiedade, e histórico familiar para qualquer condição psiquiátrica. Este estudo, realizado em uma região urbana da cidade de São Paulo, com altos índices de vulnerabilidade social, indica que a prevalência de EPs em gestantes é alta, afetando cerca de 1 em 6 mulheres. A presença de EPs associa-se fortemente com psicopatologia geral e com amplos fatores de risco. Neste sentido, a presença de EPs pode se constituir em um importante indicador de risco a ser avaliado em ambientes clínicos durante a gestação. Estudos futuros que possam investigar a sua utilidade para indicação de intervenções são necessários, assim como estudos que investiguem o curso de EPs apos o período gestacional e a sua associação com desfechos de saúde nas mulheres e em seus filhos / This research investigated the prevalence and construct validity of psychotic experiences (PEs) during pregnancy and the risk factors in a community sample in the city of São Paulo. Sociodemographic and environmental risk factors, psychiatric disorders, domestic violence, intellectual capacity and family history of psychiatric disorders in the present and throughout life were the investigated elements. Pregnancy and delivery outcomes were also evaluated. This is a prospective research, starting in the 3rd trimester of pregnancy. The evaluation interviews were conducted by trained psychologists. For the evaluation of PEs, the brief standardized diagnostic interview tool was used - Mini International Neuropsyquiatric Interview (M.I.N.I), validated for the Brazilian reality. For the sociodemographic risk factors, both socioeconomic questionnaire (SEQ) and population density (PD) were applied and the criterion of economic classification in Brazil (CECB) was used by the Brazilian Association of Research Companies (BARC) and World Health Organization - WHO for domestic violence. The intellectual capacity evaluation was carried out, using the Wechsler Intelligence Scale for Adults, third version (Waiss-III), and the family history of mental disorders was investigated through The Family History Screen (FHS). The results indicated a prevalence of 19.22% of PEs during pregnancy and sharing the risk factors present in schizophrenia, such as urbanicity, young pregnant women, use of drugs and alcohol, socioeconomically disadvantaged, low educational level, exposure to situations of violence, the presence of psychiatric disorders such as depression and anxiety, and family history of any psychiatric condition. This research, conducted in an urban area of the city of São Paulo, with high social vulnerability, indicates that the prevalence of PEs in pregnant women is high, affecting about 1 in 6 of them. The presence of PEs is strongly associated with general psychopathology and broad risk factors. In this sense, the presence of PEs may constitute an important risk factor to be evaluated in clinical environments during pregnancy. Future researches intending to look into its usefulness for indication of interventions are needed, as well as studies to search into the course of PEs after pregnancy and its association with health outcomes for women and their children

Abstract Both genetic and biological and psychosocial environmental risk factors contribute to the aetiology of schizophrenia spectrum disorders. Among the much studied environmental risk indicators are parental Communication Deviance (CD) and the winter or spring birth of a child. Genetic and environmental risk factors do not function in isolation from each other, but gene-environment interactions play a major role in the aetiology of psychotic disorders. The aim of this doctoral thesis is to investigate the role of parental CD as a risk factor (together with other risk indicators) for thought disorders and schizophrenia spectrum disorders in an adoptive child. A systematised review was performed concerning the association between parental Communication Deviance and schizophrenia spectrum and thought disorders in offspring. A meta-analysis could only be performed for the association of parental CD with schizophrenia spectrum disorders in offspring. A large overall effect size was found (0.79, 95%CI 0.21–1.37). The studies included in the systematised review suggest that frequent parental CD and thought disorders in the offspring are connected with each other. The two original studies are based on the data derived from the total sample of the Finnish Adoptive Family Study (n=382). First, the association between parental Communication Deviance scored from individual and family Rorschach protocols and the characteristics of the adoptive child and the parents themselves was investigated. The variability of CD in the adoptive parents in individual and family Rorschach situations was most closely associated with the characteristics of the parents themselves. The association of an adoptive child’s thought and schizophrenia spectrum disorders with the child’s genetic risk for schizophrenia spectrum disorders, winter or spring birth, and parental Communication Deviance, and their interactions was also explored. The adoptive child’s thought disorders were associated only with parental CD. None of the risk indicators or their interactions predicted the adoptee’s schizophrenia spectrum diagnosis. In conclusion, the results indicate that the amount of Communication Deviance is a stable trait of an individual. It may be considered as a risk indicator for schizophrenia spectrum disorders in offspring and, with a lower level of confidence, also for thought disorders in offspring. / Tiivistelmä Skitsofreniaspektrin sairauksien varsinaisia syytekijöitä ei tunneta, mutta niillä on lukuisia sekä perimään että biologiseen ja psykososiaaliseen ympäristöön liittyviä riskitekijöitä. Nykytietämyksen mukaan riskitekijät eivät vaikuta sairauden syntyyn itsenäisesti, vaan perimän ja ympäristön vuorovaikutuksella on merkittävä osuus. Paljon tutkittuja ympäristöön liittyviä riskitekijöitä ovat lapsen talvi- tai kevätsyntymä ja vanhempien hajanainen kommunikaatio. Tässä väitöskirjassa tutkitaan vanhempien hajanaista kommunikaatiota adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien riskitekijänä. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien ja ajatushäiriöiden yhteydestä laadittiin systemaattinen katsaus. Meta-analyysi voitiin tehdä vain skitsofreniaspektrin sairauksiin liittyen. Vanhempien hajanaisen kommunikaation ja lapsen skitsofreniaspektrin sairauksien välisellä yhteydellä havaittiin olevan suuri efektikoko (0,79, 95 % luottamusväli 0,21–1,37). Katsaukseen sisällytetyt tutkimukset viittaavat siihen, että vanhempien hajanaisella kommunikaatiolla ja lapsen ajatushäiriöillä on myös yhteys. Väitöskirjan alkuperäistutkimukset perustuvat Suomalaisen adoptiolapsiperhetutkimuksen aineistoon (n= 382). Aluksi tutkittiin vanhempien yksilö- ja perhe-Rorschach-tilanteissa mitatun hajanaisen kommunikaation määrän ja lapsen ja vanhempien ominaisuuksien välistä yhteyttä. Hajanaisen kommunikaation määrän vaihtelu selittyi pääosin vanhempien ominaisuuksilla. Seuraavaksi tutkittiin adoptiolapsen ajatushäiriöiden ja skitsofreniaspektrin sairauksien yhteyttä lapsen skitsofreniaspektrin sairauksille altistavan perimän, talvi- tai kevätsyntymän ja vanhempien hajanaisen kommunikaation kanssa. Huomioon otettiin myös riskitekijöiden yhteisvaikutukset. Mikään riskitekijä tai niiden yhteisvaikutus ei ollut yhteydessä lapsen skitsofreniaspektrin sairauteen. Lapsen ajatushäiriöt olivat yhteydessä ainoastaan vanhempien hajanaiseen kommunikaatioon. Tutkimuksen tulokset osoittavat, että vanhempien hajanainen kommunikaatio on kohtalaisen muuttumaton piirre, joka on lapsen skitsofreniaspektrin sairauksien riskitekijä. Tulokset viittaavat myös siihen, että vanhempien hajanainen kommunikaatio voi olla lapsen ajatushäiriöiden riskitekijä.

INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentados / INTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herein

INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentados / INTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herein