Thèses sur le sujet « Ultra-high-risk of psychosis »

This thesis evaluates the Ultra High Risk (UHR) for Psychosis evidence, and seeks to clarify how research exploring differences demonstrated by cannabis and ketamine users on measures and tasks related to the psychosis prodrome can contribute to understanding the factors involved in this stage. The thesis also examines the literature on cognitive biases and insight in the UHR state, summarising the evidence for measures and tasks which sensitively differentiate the UHR state from other stages of Psychosis development.

The findings of this PhD provide a significant contribution to early intervention research. The ability to detect those at ultra-high risk for psychosis (UHR) has been made possible in recent years. It is well known that people with serious mental illness have poor physical health, yet prior to this PhD little was known about the physical health of UHR individuals. This PhD explores the physical health and lifestyle of the UHR group, and makes recommendations for the development of a physical health intervention. A range of methods have been used including quantitative and qualitative methods, systematic reviews and meta-analyses, and a clinical audit. Therefore, a multifaceted approach to investigate the physical health and lifestyle of UHR individuals has been taken. Papers 1-3 suggest UHR individuals are more likely to live an unhealthy lifestyle than their peers. This includes lower levels of physical activity, and higher levels of substance use (generally cannabis, tobacco and alcohol). Paper 4 contains a clinical audit showing physical health and lifestyle factors are not monitored routinely in early detection services, despite the UHR phase being an ideal opportunity to intervene. Living an unhealthy lifestyle can have a detrimental effect on physical and mental health. Papers 1-4 emphasise the need to intervene to promote a healthy lifestyle for the UHR group. In line with the Medical Research Guidelines for the development of complex interventions, a theoretical model is applied in Paper 5. The final paper presents a qualitative study with UHR individuals, their parents and clinicians to explore barriers and facilitators to living a healthy lifestyle and inform the development of a physical health intervention. A final evidence synthesis includes recommendations for future work and the clinical implications of this thesis. The findings of this PhD provide an important and timely contribution to early intervention research. Prior to this work, the physical health of UHR individuals had been largely under researched. For the first time, this PhD presents evidence to suggest individuals at ultra-high risk for psychosis experience cardiovascular risk, and there is an opportunity to intervene to promote physical health. Although not all UHR individuals will develop psychosis, many will continue to experience difficulties with their mental health. Given that this group are also more likely to live an unhealthy lifestyle, it is important to take a holistic approach to treating those at imminent risk for psychosis, considering both mental and physical health.

Individuals experiencing prodromal symptoms of psychosis have a very high risk of developing the disorder ranging from 18%-36% within three years of the first clinical presentation. Currently, it is not possible to predict which individuals will subsequently become psychotic only on the basis of their presenting clinical features. This potentially prevents the selective delivery of specialised clinical interventions to those individuals more likely to develop psychosis, which is desirable, both from an ethical point of view and for a more targeted use of available treatments. Neuroimaging may aid prediction as recent neuroimaging studies suggest that there are neuroanatomical differences in people at ultra high risk (UHR) for psychosis relative to healthy control subjects. Furthermore, within UHR cohorts, those who later develop a psychotic disorder (UHR-T, transition) often show more marked structural alteration than those that do not (UHR-NT, non-transition). However the findings have been inconsistent and this may partly reflect the use of small samples and different analytic methods. The aim of this doctoral project was to assess brain structure in individuals at UHR of psychosis using a larger sample than in previous studies. This was achieved by combining Magnetic Resonance Imaging (MRI) data from four different scanning sites and using a range of different analytic methods including voxel-based morphometry, voxel-based cortical thickness analysis and multivariate machine learning. The use of these methods allowed a comprehensive investigation of neuroanatomical differences in a large cohort and, between UHR-T and UHR-NT cases in terms of i) regional gray matter volume; ii) cortical thickness; and iii) subtle and distributed patterns of gray matter alterations. Findings suggest that there are neuroanatomical abnormalities that precede the emergence of psychosis within a distributed fronto-temporal network. In addition, UHR and healthy controls are distinguishable at the individual level based on information on the gray matter volume, whereas UHR-T and UHR-NT are distinguishable at the individual level using cortical thickness information. Nevertheless, the accuracies reported remain relatively low to be applied in real-world clinical settings. Results from this project contribute to expanding the available knowledge on the UHR population.

Recognition of the negative personal, economic and social consequences of psychosis have led to attempts to identify and intervene with those who are at ultrahigh risk (UHR) of developing psychosis with the aim of improving clinical and functional outcomes. It is important that we understand the processes occurring in this period in order to inform preventative interventions. The importance of the family in psychosis is well established with extensive evidence indicating that families are often adversely affected by caring for a family member with psychosis and that the family can influence the course and outcome of psychosis. The family may be a particularly important influence on the UHR group as they are adolescents and young adults who are likely to be living in the family home. There has however been very little research into the family environment in this group. This study aimed to improve theoretical understanding of the family environment in the UHR group by exploring the experiences of the young people and their family members during this phase. This study used a qualitative design using Grounded Theory methodology. Nine UHR young people and five family members were interviewed about their experiences of their family environment. Analysis of the data produced eight theoretical codes describing the family environment over time. These related to difficult early family experiences, difficulties negotiating life-cycle transitions, lacking a framework to understand the young person's difficulties, reaching a crisis point, reappraising roles and futures, family protecting and constraining the young person and, finally, renegotiating the young person's independence. The data describes the interaction of beliefs and behaviours between these young people and family members and the impact of the stage of psychosis, early family experiences and life-cycle stage on these interactions. The findings have implications for the development of family interventions for the UHR group.

Current understanding of ultra high risk syndromes for psychosis (UHR) has been based almost entirely on studies of clinical help-seeking populations. The current study aimed to estimate what proportion of the community would meet UHR criteria, to assess whether this was associated with a need for care, and to explore how these individuals relate to those in clinical settings. An epidemiological sample of 208 young adults (aged 18 to 35) was interviewed using the CAARMS (for positive and negative symptoms) and the SPI-A (for basic symptoms), along with measures of functioning and general psychopathology. Help-seeking was measured in relation to both clinical and informal sources of help. Comparisons were also made with a clinical UHR sample from the OASIS service in South London. Thirty individuals met symptomatic criteria for an UHR state (14 met CAARMS criteria, 12 met SPI-A criteria, 4 met both), giving an estimated community prevalence of around 13%. Of these, 66% (n = 20) reported an unmet need for care, 52% (n = 15) had sought some form of help and 33% (n = 9) had engaged in clinical help-seeking. Help-seeking and distress were most associated with negative symptoms and least associated with basic symptoms. Nevertheless, these community UHR subjects were less functionally impaired [t(63) = 3.30, p = .003] and had less severe positive [z = -4.21, p < .001], negative [z = -2.63, p = .017] and general psychopathology [z = -2.74, p = .019] than those already attending clinical services. Results suggest that the UHR criteria can identify something clinically meaningful even in the general population, and that there may currently be individuals who would benefit from outreach by existing UHR services. However, results also suggest that the current focus on positive symptoms may be insufficient for identifying those in need of care.

Background: It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating. Methods: Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n=3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors. Results: Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89–2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006–.0244), cannabis use (P < .0009), and any drug use (P < .0008). Conclusion: Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities.

Background: It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating. Methods: Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n=3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors. Results: Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89–2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006–.0244), cannabis use (P < .0009), and any drug use (P < .0008). Conclusion: Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities.

Patients in the early phase of psychosis show impairments of emotional processing. These patients also demonstrate neuroanatomical and neurofunctional abnormalities which are similar to those in patients with schizophrenia in regions that are involved in emotional processing. Impaired emotional processing is reported, albeit in an attenuated form, in individuals with an Ultra High Risk (UHR) for psychosis. To date however, few studies have specifically examined the neural substrate of emotional processing in the early and prodromal phase of psychosis. The effective integration of emotional information is extremely important for interpersonal interactions and daily social functioning; but the disturbances of integration of multisensory emotional information and the associated neural processes in patients with the early phase of psychosis remain unclear. Moreover, there are no studies that have examined the integration of emotional information in the early and prodromal phase of psychosis. To do this I developed a Multisensory Emotion Recognition and Integration Task (MERIT). In an fMRI experiment and examined the neural substrate for emotion recognition and multisensory integration and the possible alteration in sixteen UHR subjects and eighteen patients with first episode of psychosis (FEP), in contrast with twenty-one healthy controls (HC). FEP patients demonstrated impairments in both unisensory and multisensory emotion recognition, and reduced activation in the brain areas associated with emotional recognition. In UHR subjects, such alterations were less pronounced than in FEP patients. Both FEP and UHR groups did not show a significant alteration in the brain areas associated with integration, but FEP patients failed to deactivate areas that may have been associated with irrelevant visual stimuli, and areas associated with the default mode brain network. A speculative model proposes that the posterior superior temporal area is important for integrating emotional information, and its activation can be modulated by modality-specific attention. These results are in part consistent with the notion that, relative to HCs, FEP patients show neurofunctional alterations in emotional processing regions that are qualitatively similar to those previously observed in schizophrenia patients. UHR subjects showed altered behavioural performance and brain activation at an intermediate level between those in HC and FEP groups. This raises the possibility of establishing neurofunctional biomarkers for emotional processing that could be used to identify UHR subjects who have a higher risk of frank psychosis, a prospect which could be investigated in future prospective and longitudinal studies.

A modern conceptualization of psychotic disorders is as neurodevelopmental disorders, with different stages characterized by discrete clusters of symptoms. This conceptualization includes a stage of pre-psychotic prodrome, a target of contemporary research as an attempt to intervene before the development of psychosis. However, these at-risk individuals rarely present to the mental health services before transitioning into psychosis, even more so for male patients. In this study, a method of inductive thematic analysis has been employed to inquire into the pathways to care for young men at Ultra-High Risk (UHR) for psychosis to gain knowledge of- and generate hypotheses about pathways to care for this group. Data was collected using semi-structured interviews (n = 9) over video conference or telephone. Three core-themes were developed as “Willingness to Disclose Distress”, “The Gatekeeping Confidant”, and “The Boiler”, with “Openness” as a core organizing category permeating the core-themes. Together, the themes represent findings on both the importance of relations in help-seeking, as well as how the young men commonly employ non-disclosure, and how this lack of openness delays pathways to care, often resulting in adversities for the participants. Findings provide implications for further inquiry into how to increase the likelihood of young men to disclose distress, as well as providing additional rationale for the development of Mental Health Literacy in the public to make peers as well as participants more able to recognize symptoms of the pre-psychotic prodrome, when, where and how to seek help.

Background: Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been observed in psychotic disorders. Abnormal levels of the HPA axis hormone, cortisol, are associated with various cognitive processes and cognitive deficits are a key feature of psychosis. The cortisol awakening response (CAR) has been shown to be abnormal in first episode psychosis (FEP) patients but has not been explored in individuals at ultra high-risk (UHR) for developing psychosis. Objectives: The objectives of the following set of studies were to examine the relationship between the CAR and cognitive function in FEP patients and in UHR individuals. In addition, based on established sex differences in both HPA axis activity and psychosis, the effect of sex on this relationship was also explored. Methods: Eighty-two FEP patients, 28 individuals at UHR for psychosis, and 31 community controls were recruited to participate in the two studies. Saliva samples were collected to assess the CAR and a neuropsychological battery was administered to determine performance on six cognitive domains. From these, a global cognition score was also calculated. Results: FEP patients, but not UHR individuals, had a blunted CAR compared to controls and male FEP patients had a more blunted CAR than female FEP patients. A more blunted CAR was associated with a more severe deficit in verbal memory and a lower global cognition score only in female FEP patients. Conclusion: The results suggest that although UHR individuals show deficits in certain cognitive domains, the CAR remains in tact, and there is no association between the two. However, a blunted CAR plays a role in cognitive function for female FEP patients. This may have implications for time and gender specific interventions aimed at stabilizing HPA axis activity.
Contexte: La dérégulation de l'axe hypothalamo-hypophyso-surrénalien (HHS) a été observée dans les troubles psychotiques. Des niveaux anormaux de cortisol, une des hormones de l'axe HHS, sont associés à divers processus cognitifs et les déficits cognitifs sont un élément clé de la psychose. Des études démontrent que la sécrétion de cortisol au réveil (SCR) est anormale dans le premier épisode psychotique (PEP) des patients, mais n'a pas été explorée chez les personnes à très haut risque (THR) de déveloper une épisode de psychose. Objectifs: Les objectifs de ces diverses études étaient d'examiner la relation entre la SCR et la fonction cognitive chez les patients PEP et chez les personnes THR. En dépit des différences de sexe connues sur l'axe HPA et la psychose, l'effet du sexe sur cette relation n'a pas été étudié. Méthodes: Quatre-vingt-deux patients PEP, 28 individus à THR pour la psychose, et 31 contrôles communautaires ont été recrutés pour participer dans les deux études. Des échantillons de salive ont été prélevés pour évaluer la SCR et une batterie de tests neuropsychologiques a été administrée pour déterminer les performances sur six domaines cognitifs. De ceux-ci, un résultat cognitif global a également été calculé. Résultats: Les patients PEP, mais pas les individus THR, avaient une SCR atténuée par rapport aux témoins contrôles et les patients masculins PEP avait une SCR plus atténuée que les patients PEP féminin. Une SCR plus atténuée a été associée à un déficit plus sévère de la mémoire verbale et un résultat inférieur de la cognition globale uniquement chez les patients PEP féminins. Conclusion: Bien que les individus THR présentent des déficits dans certains domaines cognitifs, les résultats montrent que la SCR reste intacte et qu'il n'y a aucun lien entre les deux. Toutefois, une SCR atténuée joue un rôle dans la fonction cognitive chez les patients PEP féminins. Cela peut avoir des implications pour les interventions spécifiques au sexe et au temps visant à stabiliser l'activité de l'axe HHS.

La psychose est un syndrome apparaissant progressivement à l’adolescence chez des individus à risque selon un processus dynamique appelé transition psychotique. Ces individus à risque sont repérables cliniquement mais les données biologiques actuelles sont insuffisantes pour expliquer l’apparition de la psychose. Au cours de cette thèse, nous avons cherché à identifier les facteurs biologiques responsables de ce processus. Les hypothèses permettant d’expliquer la transition psychotique privilégient l’interaction gène x environnement, sous-tendue par des mécanismes épigénétiques. Nous avons mené une étude des modifications de la méthylation de l’ADN et de la transcription à l’aide de techniques de biologie moléculaire et de bio-informatique à l’échelle pan-génomique. La transition psychotique semble être liée à des modifications de méthylation et de transcription de gènes impliqués dans des mécanismes comme le guidage axonal ou la régulation du stress oxydatif. Ces modifications longitudinales pourraient refléter l’influence de l’environnement. Les facteurs environnementaux pourraient déréguler l’axe biologique du stress dès les phases précoces de la maladie, comme le suggère l’augmentation de la sécrétion de cortisol basal que nous avons montré chez les individus à risque. En outre, il est probable que des spécificités au niveau des gènes et des processus régulant l’épigénome soient également impliquées dans cette réponse individuelle à l’environnement. Nous avons montré l’importance du métabolisme mono-carboné au moins dans un sous-groupe spécifique de patients. Ces résultats doivent être répliqués et étendus dans d’autres paradigmes pour valider l’implication de ces processus dans la transition psychotique. En cas de confirmation, ces voies biologiques pourraient s’avérer être des pistes intéressantes pour développer des thérapeutiques ciblées et relever le défi de la prévention de la psychose chez des individus à risque
Psychosis is a progressive mental disorder which normally occurs during adolescence in at-risk subjects following a dynamic process termed “psychotic transition”. These at-risk subjects are clinically identifiable but biological data are still insufficient in explaining the onset of psychosis. Throughout this thesis, we aim to identify biological factors implicated in this pathophysiological process. Current hypotheses explaining the psychotic transition favor the interaction between genes and the environment mediated by epigenetic mechanisms. We conducted studies examining methylomic and transcriptomic changes during psychotic transition using molecular biology and bioinformatics techniques at a whole genome scale. Our results suggest that psychotic transition may be linked to methylomic and transcriptomic changes in genes implicated in axon guidance or oxidative stress. These longitudinal changes could be related to environmental factors. Some of these factors could deregulate the hormonal stress response at the earliest phases of psychosis. Indeed, our results show that secretion of basal cortisol is increased in prodromal individuals. Moreover, it is likely that genes and processes regulating epigenetic modifications are also implicated in the individual response to the environment. We have shown the importance of the one-carbon metabolism for at least one sub-group of patients affected by psychosis. Our results should be replicated using other paradigms in order to definitively validate the implication of these various actors in the psychotic transition. If confirmed, knowledge of these biological mechanisms could lead to the development of targeted therapeutics to prevent psychosis in at-risk individuals

Background. There is strong evidence that supportive social relationships are associated with positive outcome variables in individuals with a long-standing psychotic disorder. Furthermore, evidence suggests that the social relationship deficits characteristic of psychosis are already apparent in the very early stages of the disorder. However, so far no comprehensive answer has emerged to the question of whether supportive social relationships have similar positive effects at psychosis onset, and which qualitative and functional aspects of support are attributed to these effects. A systematic review of the literature was therefore conducted to establish what is currently known about the relationship between perceived social support and outcomes in early psychosis. Method. Medline, Embase and PyschINFO were searched for studies investigating perceived social support in ‘ultra-high risk’ (UHR) and first episode psychosis samples using the expressions (‘schizophreni*’ or ‘psychosis’ or ‘psychotic disorder’) and (‘first episode’) and (‘ultra high risk’ or ’UHR’ or ‘clinical high risk’ or ‘at risk mental state’ or ‘ARMS’) and (‘social support’). Findings were synthesised using non-quantitative approaches. Results. At total of 3006 citations were screened and 11 studies were identified that met inclusion criteria. There was marked methodological heterogeneity, which limits the capacity to draw direct comparisons between the studies. Nonetheless, the existing literature suggests perceived social support has protective effects on service user outcome. These effects may be a function of support from friends and confidantes rather than from family members, and emotional support may be more important than practical support. Conclusion. Perceived social support appears to have beneficial effects on symptom severity, functioning, and levels of remission and quality of life in early psychosis. There is a need for more robust and comparable studies that employ valid and reliable measures of perceived social support and its multidimensional domains to evaluate the effects further and determine the specific mechanisms responsible for these effects. Future studies should also address possible mediating and moderating effects of perceived social support on known risk factors for psychosis.

Two main psychopathology-based approaches to detection of the prodrome have emerged; the Ultra High Risk (UHR) and Basic Symptom approaches. Conversion risk varies between studies using these approaches and in one centre conversion rates are reported to be decreasing year on year. There is a need examine the conversion risk across studies to establish a pooled estimate of risk for instruments designed to detect the prodrome of psychosis. To maximise the detection of those thought to present a risk of psychosis the Lancashire Early Assessment and Detection (LEAD) clinic uses an UHR instrument, the Comprehensive Assessment of at Risk Mental States (CAARMS) and A Basic Symptom instrument, the Schizophrenia Proneness Instrument (SPI-A). The thesis had two broad aims 1) to conduct a systematic review with meta-analysis of the research field to date and identify areas for further research, 2) to establish the accuracy of the LEAD clinic predictions. The meta-analysis involved a systematic search of MEDLINE, EMBASE, PsychINFO and CINHAL identifying studies of psychopathology-based instruments for the detection of the psychosis prodrome. The service evaluation examined for conversion to psychosis in patients examined for Basic Symptoms (SPI-A), attenuated positive symptoms (CAARMS), schizotypy (SPQ-A) and social functioning (SOFAS).The meta-analysis found that both the UHR and Basic Symptom approaches yield similar results. The differences in the positive predictive values (PPV) of the two approaches were not significant (Basic Symptoms, 0.34, UHR 0.25). The service evaluation found over a third (n=58) of referrals to the LEAD clinic to be psychotic at baseline and sixty-four patients to have an at risk mental state (ARMS). Conversion risk for CAARMS was 36.67%. and was 28.57% for SPI-A. The COGDIS criterion of SPI-A was found to be the most predictive with a PPV of 0.43, a sensitivity of 0.80. When patients met a combination of both COGDIS and CAARMS the likelihood ratio increased to 5.25 although the sensitivity was low (0.47).Overall, the findings of the thesis indicate that both the Basic Symptom and UHR approaches are valid for use in routine clinical settings for the assessment of psychosis risk. The thesis found that a combination of both approaches could provide future opportunities research. The SPQ-A schizotypy assessment was found to correlate with the attenuated symptom criterion of CAARMS and evidence suggests that the SPQ-A score increases closer to transition. The SPQ-A could offer opportunities for developing efficient methods of monitoring progression of prodromal symptoms.

Background. Chronic exposure to stressors in childhood has been linked with heightened risk of developing symptoms of psychosis in both clinical and non-clinical populations. The association has been explicated with reference to developmental alterations in biological and psychological systems. One such stressor, being bullied in childhood, has been the focus of recent investigations. The current study endeavoured to systematically review the available evidence from studies purporting to investigate the association between childhood bullying and psychosis symptomatology. Method. A search of PubMed, Medline, PsycInfo, Embase, Scopus and Web of Science electronic databases, alongside manual searching and cross-referencing, was carried out. The quality of available evidence for and against the association was assessed using quality assessment tools found in the literature. Results. Meeting the study’s inclusion criteria were 30 studies (eighteen cross-sectional, twelve cohort). Longitudinal studies, by design, provided higher quality evidence - particularly those which examined specifically the association between the variables of interest. However, preselected key confounding variables were not always taken into account, highlighting that the association is not unequivocal and that further research is warranted. Cross-sectional studies provide lower quality of evidence (of greater variability) where severe limitations regarding the validity and generalisability of findings must be taken into account. Conclusions. Evidence suggests that the association between experience of bullying in childhood and onset of psychotic or psychotic-like symptoms of clinical and non-clinical severity is tenable. However, future research needs to re-examine the association while minimising methodological limitations including confounding variables and definitional issues. Establishment of an association warrants investigation of the mechanisms which potentially underlie it; the pre-existing, small research base on mediators and moderators of the relationships requires further attention.

La mémoire autobiographique est vue comme un ensemble d'informations et de souvenirs personnels permettant de construire un sentiment d'identité. Elle se développe progressivement et apparaît très sensible aux pathologies neurodéveloppementales. La mémoire autobiographique est intimement liée au Soi lui permettant d'encoder et de récupérer toutes ses représentations et expériences. Ainsi, le Soi se constitue d'aspects explicites comprenant la mémoire autobiographique mais également d'aspects plus implicites relatifs aux expériences corporelles du sujet. L'atteinte des aspects implicites et explicites du Soi pourrait rendre compte de certains symptômes psychotiques et des difficultés d'adaptation des patients atteints de schizophrénie. La schizophrénie est une pathologie neurodéveloppementale qui débute à la fin de l'adolescence mais qui pourrait puiser son émergence dans des stades bien plus précoces. Le premier épisode psychotique qui signe l'entrée dans la phase active de la maladie est généralement précédé par une phase « prodromique » où des symptômes cliniques sont présents à un niveau infraliminaire du seuil de psychose. Ces sujets sont qualifiés de sujets à ultra haut risque de psychose (UHR). Les troubles du Soi sont bien documentés dans la schizophrénie, néanmoins très peu de données sont disponibles concernant les sujets UHR. Le but de cette thèse est multiple : (i) mesurer l'impact des anomalies neurodéveloppementales sur la mémoire autobiographique, (ii) objectiver des déficits de la mémoire autobiographique dès la phase prodromique, (iii) évaluer l'ensemble des composantes du Soi afin d'investiguer leurs interactions et l'impact des anomalies développementales sur celles-ci. Nous avons ainsi effectué trois études. Notre première étude a investigué le lien entre le poids des anomalies neurodéveloppementales et la mémoire autobiographique en comparant deux pathologies neurodéveloppementales, une à début tardif : la schizophrénie, et l'autre à début précoce : les troubles du spectre autistique. Nous avons pu mettre en évidence un pattern de performances similaires entre les deux populations bien que les mécanismes responsables des troubles en mémoire autobiographique apparaissent distincts. Dans notre deuxième étude, nous avons comparé les performances autobiographiques de patients atteints de schizophrénie par rapport à celles de sujets UHR. Nos résultats révèlent un déficit de la mémoire autobiographique aussi sévère chez les sujets UHR que chez les patients atteints de schizophrénie mettant ainsi en évidence une atteinte de cette fonction en amont du premier épisode psychotique. Dans la lignée de ces résultats, nous avons conduit une troisième étude. Le but étant de situer la mémoire autobiographique dans un contexte plus large, celui du Soi, tout en intégrant une composante développementale. Nous avons élaboré et proposé une batterie d'investigation examinant différents aspects du Soi implicites et explicites, combiné à l'évaluation d'anomalies du neurodéveloppement. Celle-ci a été administrée chez des sujets UHR en comparaison à des patients atteints de schizophrénie. Au final, nos résultats révèlent un impact de la charge neurodéveloppementale sur les différents aspects du Soi, la pertinence d'investiguer au sein d'un même protocole ces différents aspects et la présence d'anomalies du Soi déjà présents chez les sujets UHR, constituant potentiellement des marqueurs prédicteurs de transition psychotique et permettant d'améliorer la détection précoce de ces sujets et leur prise en charge
Autobiographical memory is delineated as a set of personal information and experiences to build a sense of identity. It develops gradually and appears very sensitive to neurodevelopmental disorders. Autobiographical memory is intimately linked to the self, enabling it to encode and retrieve all its representations and experiences. Thus, the self is constituted of explicit aspects including autobiographical memory but also by more implicit aspects relating to the subject's body. Implicit and explicit self-aspects alterations may account for certain psychotic symptoms and adaptation difficulties in patients with schizophrenia. Schizophrenia is a neurodevelopmental disorder that begins at the end of adolescence but which could emerge in much earlier stages. The first psychotic episode that signs the beginning of the active phase of schizophrenia is usually preceded by a "prodromal phase" during which clinical signs are present at a sub-threshold level. Individuals experiencing these signs are considering as Ultra High Risk of psychosis (UHR). Self-disorders are well documented in schizophrenia, however very little is known regarding UHR subjects. The aim of this thesis is multiple: (i) to measure the impact of neurodevelopmental anomalies on autobiographical memory, (ii) to objectify autobiographical memory deficits in the prodromal phase, (iii) to evaluate all the self-components in order to investigate their interactions and the impact of developmental anomalies. We have conducted three studies. Our first study investigated the relationship between neurodevelopmental anomalies and autobiographical memory by comparing two neurodevelopmental disorders, one with late onset: schizophrenia and the other with early onset: autism spectrum disorders. Results revealed a pattern of similar performances between the two populations although the mechanisms responsible for autobiographical memory impairment do not appear the same. In our second study, we compared the autobiographical performances of patients with schizophrenia compared to those of UHR subjects. Our results highlighted a deficit of autobiographical memory as severe in UHR subjects as in patients with schizophrenia, thus revealing an impairment of this function upstream of the first psychotic episode. In line with these results, we conducted a third study. The aim was to situate the autobiographical memory in a wider context, the multi-componential Self, while integrating a developmental component. We developed and proposed a battery investigating different self-components, combined with the assessment of neurodevelopmental anomalies. This battery was administered in UHR subjects compared to patients with schizophrenia. Finally, our results reveal an impact of neurodevelopmental abnormalities on the different self-aspects, the relevance of investigating these different self-aspects within the same protocol and the presence of self-abnormalities already present in the UHR subjects, constituting potentially predictive marker of psychotic transition and improving the early detection of these subjects and the development of healthcare and reinsertion programs

Background. Impaired insight, or unawareness of illness, is a common symptom of schizophrenia. Clinical insight is awareness of having a mental disorder; cognitive insight is ability to self-reflect (self­reflectiveness) and certainty in cognitions (self­certainty). In schizophrenia insight is associated with brain function and improving insight is a potential early intervention point. This study investigated whether insight is impaired in youth at ultra high-risk (UHR) for psychosis, and if it is related to major brain networks. Methods. Data from a larger UHR study was used, including 55 UHR adolescents and 55 controls assessed with the Structured Interview of Prodromal Symptoms, MATRICS Consensus Cognitive Battery, Scale to Assess Unawareness of Mental Disorder, and Beck Cognitive Insight Scale, as well as resting state functional MRI scans. UHR and control groups were tested for differences in self-reflectiveness and self-certainty, and correlations between insight dimensions and clinical and cognitive measures. Functional connectivity was calculated for the default mode, the cingulo-opercular, and central executive networks and regressed on participants’ reported clinical and cognitive insight, while covarying for head motion. Results. Self-reflectiveness was higher in the UHR group (d = 1.28), but the groups did not differ in self-certainty (d = 0.28). Among UHR, poorer clinical insight was related to greater symptom severity. Default mode connectivity was negatively correlated with self-reflectiveness (R2 = .091) and clinical insight (R2 = .399) in UHR, but no such correlations were found in controls. Cerebello-prefrontal cortex connectivity was negatively associated with self-certainty in the UHR group (R2 = .089 - .138). Conclusions. Default mode connectivity appears to be associated with the facets of insight concerning self-awareness, whereas cerebello-prefrontal connectivity appears to be associated specifically with self-certainty. This is the first study to relate major brain networks to insight before the onset of psychosis, and is consistent with models proposing that different facets of insight are related to self-awareness and executive functioning through networks associated with these processes.

Professional Doctorate - Doctor of Clinical Psychology
Background: It has been demonstrated recently that it is possible to identify individuals suffering from ‘at-risk mental states’ (ARMS) who, in the absence of treatment, are likely to develop a psychotic disorder within a year. This increase in detection ability has increased confidence that preventative interventions in psychotic disorders are a realistic proposition in clinical settings. Only three randomised controlled trials of interventions for the at-risk population have been published to date, with promising results. Two of them suggest that it is possible to prevent, or at least delay, transition to psychosis utilising Cognitive Behavioural Therapy (CBT). However, these trials have not adequately addressed treatment fidelity which is vital in allowing accurate and valid conclusions to be drawn from treatment outcome research. Method: The Detection, Evaluation and Psychological Therapy (DEPTh) project, a single blind randomised controlled trial, was designed to compare the effectiveness of CBT and a control psychotherapy, Non Directive Reflective Listening (NDRL), in ameliorating ARMS and delaying or preventing transition to psychosis. Treatment fidelity (adherence and competence) to both interventions was assessed using three established measures: The Cognitive Therapy Scale: CTS; The Cognitive Therapy for Psychosis Scale: CTS-Psy; and the Working Alliance Inventory Shortened Observer Rated Version: WAI-O-S. In addition, a new measure, the Cognitive Therapy for At Risk Populations Adherence Scale (CTARPAS) was developed, piloted and revised by the investigator and colleagues to rate therapist adherence to the French and Morrison (2004) model of cognitive therapy for individuals at high risk of developing psychosis that was used to guide the CBT intervention in the DEPTh project. 55 sessions (35 of the CBT intervention and 23 of the NDRL intervention) from a total of 21 participants were rated for fidelity. Results: The agreement between two independent raters was very high on most of the items of the CTARPAS, CTS, CTS-Psy and the WAI-O-S, for both the CBT and the NDRL interventions. Therapists delivering the CBT intervention had low mean scores on the CTARPAS which was most likely due to participants rarely discussing psychotic or attenuated psychotic symptoms. Therapists delivering the CBT intervention were rated as highly competent on the CTS. Therapists delivering the NDRL intervention were rated as adherent and competent. There were significant variations in CTARPAS ratings in the CBT intervention over the stages of therapy (early, middle and late), but there was no variation in ratings on any other measure in either intervention over the stages of therapy. High correlations were found between the CTS and the CTS-Psy. Discussion: This was the first study to investigate treatment fidelity in a randomised controlled trial of CBT and a control psychotherapy for the at-risk population. A new measure, the CTARPAS, was developed and used in this study and has the potential to be utilised in future investigations. The overall results from this study add significantly to the knowledge base in the field of indicated prevention and highlight the importance of treatment fidelity in treatment outcome research.

Primary and secondary prevention strategies have been addressed in several fields of medicine, but early detection in psychiatry still remains a grey zone, also in psychosis. Serious mental illnesses share an early presentation, with a typical beginning during adolescence for the 75% of them. The personal and societal impact of such disorders makes early detection and intervention a crucial issue, in the attempt to prevent significant consequences on individual functioning. Staging models have been developed in order to use a preventative approach, targeted at avoiding the onset and/or progression of serious mental disorders (especially of psychosis), with treatment regimens selected according to stage and individual profile risk factors. Staging allows the introduction of effective treatment in early illness phases, by means of placing individuals on a continuum in the context of the disorder progression. This goes along with the assumption that administering treatments during early illness stages could also modify the individual risk of disease progression. Although the first models were mainly applied to psychosis, the concept of staging has been progressively applied to severe psychiatric disorders, in the attempt to define early clinical phenotypes showing an enhanced risk of progression into chronic and recurrent phases of such disorders. In this research, our interest was focalized on early detection of psychosis (specifically, of adolescents and young adults with First Episode Psychosis [FEP] or at Ultra-High Risk [UHR] of psychosis). A 2-step identification procedure was proposed. For the first (“screening”) step, different instruments were described and were analyzed in their psychometric characteristics. These screeners can also be used in different settings (e.g. the “Checklist per la Valutazione dell’Esordio Psicotico [CVEP] in general medical practice; the Prodromal Questionnaire-Brief version [PQ-B], the 16-item Prodromal Questionnaire [PQ-16] or the Aberrant Salience Inventory [ASI] in triage services allocated in general child/adolescent and adult mental health centers). The second step included an in-depth assessment using clinical interviews specifically developed for the early detection of psychosis and the psychosis risk stratification (such as the CAARMS).

Growing attention has been dedicated by researchers and practitioners to early identification and intervention on young individuals considered as at ultra-high-risk (UHR) of a first psychosis episode. Cognitive behavioural therapy (CBT) has shown to be the first-line treatment strategy. However, there is a small number of trials on its efficacy. UHR groups who do not make transition frequently report poor functioning and secondary symptoms, such as depression and anxiety. Existing trials focused on psychosis prevention as a dichotomous outcome without sufficiently targeting additional outcomes. Despite it has been linked with frank psychosis, worry has not been considered as outcome. Primary objective of the current study was (a) to assess whether a CBT modular protocol was able to reduce or delay risk of transition to psychosis in a group of UHR help-seeking individuals after 6 months (post-treatment) and 14-months (follow-up) compared with treatment as usual as a control condition. Secondary objectives were (b) to compare the CBT intervention with the control condition on secondary outcomes, including depression, anxiety, worry and global functioning. Participants were included if they were 16-35-year old and met criteria for At-Risk-Mental State (ARMS) at the Comprehensive Assessment of At-Risk-Mental States (CAARMS). Fifty-eight individuals recruited from mental health services (mean age= 25.51, SD= 6, 67.20% males) were randomly assigned to CBT or control condition. The CBT modular protocol consisted of 30 weekly sessions with multiple components including engagement and goal setting, psychoeducation on psychotic experiences, (meta)cognitive restructuring, intervention on depression, worry, social anxiety and skills. Kaplan-Meier survival statistics were used to analyse the primary outcome. Participants lost to followup were coded conservatively as non-converters. In the group that did not make transition, secondary outcomes were analysed by ANCOVA. Overall, 7 participants (12.10%) at post-treatment and 11 (19%) at 14-month follow-up cumulatively made the conversion to psychosis. In the CBT group, the number of individuals who made cumulative conversion to psychosis (n= 4, 10.30%) at 14-month follow-up was lower than in the control group (n= 8, 27.60%), despite this difference was at a borderline significance level (Log rank test χ2(1)= 3.66, p= 0.05). In the CBT group, a higher number of participants achieved remission than in the control group on secondary outcomes at post-treatment (75% vs 38.10% for both depression and anxiety) [χ²(1)= 6.25, p< 0.05] and also at follow-up. However, a significantly greater effect of CBT than control condition on depression, anxiety, worry and functioning was not found when these outcomes were considered as continuous. CBT seems to be an option of intervention able to reduce drop out among UHR individuals and to some extent also prevent the risk of a first episode with some benefits on secondary outcomes such as anxiety and depression when levels on these outcomes are clinically significant. Further research is required to examine additional strategies targeting worry and functioning. Clinical implications, limitations and future directions are discussed.

Alterations of the kynurenine pathway are linked to the pathophysiology of schizophrenia. Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Its function in the CNS is largely unexplored. Moreover, xanthurenic acid (XA), produced by transamination of 3-hydroxykynurenines, was found to activate mGlu2 metabotropic glutamate receptors. Here, we have explored the interaction between XA and mGlu2/3 and between CA and mGlu4 receptors using in a battery of vivo models. Moreover, we assessed serum levels of kynurenine metabolites in a large cohort of patients affected by schizophrenia, their first-degree relatives, healthy controls and Ultra-High Risk (UHR) for psychosis subjects. Since CA was not detectable in serum of healthy controls, we measured CA levels in autoptic brain tissue of 23 individuals affected by schizophrenia and 26 age-matched controls.