Dissertations / Theses on the topic 'Schizophrenia – Epidemiology'

This Thesis describes the epidemiology of schizophrenia and related disorders in the defined catchment area of Camberwell, SE London, UK, over the period 1965 to 1984. Cases were ascertained through the comprehensive Camberwell Cumulative Psychiatric Case Register. All first-contact patients with a Register diagnosis of any non-affective non-organic psychotic illness were included in the study. Diagnostic uniformity was ensured by rediagnosis of all cases (n=531) using the computerised OCCPI system, which facilitates rediagnosis according to a wide range of diagnostic criteria. Trends in the incidence of non-affective functional psychoses over the two decades during which the Camberwell Register was operational, are explored. The findings, of a rising rate of illness in Camberwell, are discussed in terms of changes in the demography of the general population over the years, and suggestions offered for discrepancies with other studies of time trends in schizophrenia, particular emphasis being placed on changes in the ethnic composition of Camberwell over this period. A case-control study design is used to explore whether the rising incidence of the illness in the area is due solely or largely to drift into the area of ill individuals, or whether some of the variance can be explained in terms of a pernicious inner-city effect operating during early development (in utero or in early childhood). The findings of an excess of schizophrenia patients actually having been born in the inner city suggests that something about poor households in the inner city might predispose to the illness in later life. This is discussed in the general framework of the neurodevelopmental hypothesis of schizophrenia, which proposes that at least some individuals have a form of illness consequent upon subtle damage to the developing brain. A major focus of the analyses is gender differences in schizophrenia, and late onset schizophrenia. Early-onset males were particularly likely to fulfil stringent diagnostic criteria for the illness, and to show premorbid dysfunction. The results are interpreted in the neurodevelopmental framework, and reference made to differences in male and female brains in their vulnerability to neurodevelopmental illnesses in general. Taking this theme forward, a form of factor analysis called latent class analysis is used to further explore the notion of different subtypes of schizophrenia, one of which is an early-onset severe male-predominant form (theoretically consequent upon neurodevelopmental deviance). The analyses resulted in a "best fit" model of three subtypes, one an early-onset male-predominant type associated with premorbid dysfunction ("neurodevelopmental" type); a later-onset "paranoid" type; and an affect-laden type exclusive to females ("schizoaffective" type). There were associations with a number of variables of potential importance in terms of aetiology, namely an association of the "neurodevelopmental" type with a family history of schizophrenia and obstetric complications; an association of the "paranoid" type with winter birth; and of the "affective" type with a family history of psychiatric disorder other than schizophrenia (predominantly affective disorder). This typology does not adequately account for those patients with a late (over 45 years), or very-late onset of illness (over 60). Phenomenological, premorbid, and other differences between early- and late-onset patients are analysed, and the results discussed in the broader framework of the literature on late-onset non-affective psychoses.

(Truncated abstract) The aims of this thesis are: (i) To estimate the prevalence of psychiatric illness among persons with intellectual disability and, conversely, the prevalence of intellectual disability among persons with a psychiatric illness; (ii) To describe the disability and service utilisation profile of persons with conjoint disorder; (iii) To examine, in particular, intellectual disability co-occurring with schizophrenia; and (iv) To explore the role of hereditary and environmental (specifically obstetric) risk factors in the aetiology of (i) intellectual disability and (ii) intellectual disability co-occurring with psychiatric illness. This thesis has a special interest in the relationship between intellectual disability and schizophrenia. Where data and sample sizes permit, it explores that relationship at some depth and has included sections on the putative nature of the link between intellectual disability and schizophrenia in the introductory and discussion chapters. To realise its objectives, the thesis comprises a core study focusing on aims (i) – (iii) and a supplementary study whose focus is aim (iv). It also draws on work from an ancillary study completed prior to the period of candidacy...This thesis found that, overall, 31.7% of persons with an intellectual disability had a psychiatric illness; 1.8% of persons with a psychiatric illness had an intellectual disability. The rate of schizophrenia, but not bipolar disorder or unipolar major depression, was greatly increased among cases of conjoint disorder: depending on birth cohort, 3.7-5.2% of individuals with intellectual disability had co-occurring schizophrenia. Down syndrome was much less prevalent among conjoint disorder cases despite being the most predominant cause of intellectual disability while pervasive developmental disorder was over-represented. Persons with conjoint disorder had a more severe clinical profile including higher mortality rates than those with a single disability. The supplementary study confirmed the findings in the core body of work with respect to the extent of conjoint disorder, its severity, and its relationship with pervasive development disorder and Down syndrome. Moreover, the supplementary study and the ancillary influenza study indicated a role for neurodevelopmental insults including obstetric complications in the adverse neuropsychiatric outcomes, with timing of the insult a potentially critical element in defining the specific outcome. The supplementary study also added new information on familiality in intellectual disability. It found that, in addition to parental intellectual disability status and exposure to labour and delivery complications at birth, parental psychiatric status was an independent predictor of intellectual disability in offspring as well as a predictor of conjoint disorder. In conclusion, the facility to collect and integrate records held by separate State administrative health jurisdictions, and to analyse them within the one database has had a marked impact on the capacity for this thesis to estimate the prevalence of conjoint disorder among intellectually disabled and psychiatric populations, and to understand more about its clinical manifestations and aetiological underpinnings.

Background: Schizophrenia is a chronic, debilitating mental disorder characterized by positive (e.g., hallucinations, delusions) and negative (e.g., catatonia, flat affect) signs and symptoms. Many studies suggest that individuals born in winter or spring months are at increased risk for schizophrenia. Study Objectives: 1) To determine whether season of birth affects risk for schizophrenia in the Irish Study of High Density Schizophrenia Families (ISHDSF). 2) To examine, by computer simulation, power to detect genetic associations with schizophrenia under a variety of conditions and using different analytic strategies. 3) To test whether specific genes are associated with schizophrenia in the Irish Case Control Schizophrenia Study (ICCSS), using different analytic strategies to account for season of birth. Methods: A case-control design was used to examine the relationship between schizophrenia and season of birth. Cases were individuals from the ISHDSF diagnosed with schizophrenia. Controls were the general population of Ireland, with data provided by Ireland’s Central Statistics Office (CSO). The birth frequencies for each month or quarter were compared in the two groups by a chi square test. Computer simulations were conducted to examine power to detect schizophrenia susceptibility loci using either all cases or only cases born in high-risk months, under different conditions and models for how genetic risk and season of birth interact to influence risk for schizophrenia. Data for six genetic markers from the ICCSS were analyzed for evidence of association, using all cases, and then using only cases born in high-risk months. Setting and Study Participants: ISHDSF families were ascertained through inpatient psychiatric care facilities serving >95% of the Irish population. Diagnoses were established using DSM-III-R criteria, and birthdates were recorded for all individuals. The Irish CSO provided aggregate, population-level data for number of births in Ireland by month for the years 1976-2000 and by quarter for the years 1900-2000. The ICCSS is a sample of schizophrenic and control individuals who have been genotyped at many loci across the genome. Schizophrenics were ascertained through in- and outpatient psychiatric facilities, had diagnoses verified by an expert, and their birthdates recorded. Controls were selected from several sources, e.g. blood donation centers, and denied any lifetime history of schizophrenia. For each subject in the ICCSS, all four grandparents were born in Ireland or the United Kingdom. Results: Number of births in each month was compared for schizophrenics in the ISHDSF and general population controls, resulting in a chi square of 19.44 (p value ~ 0.054, 11 df). Simulations revealed that, in some circumstances, power to detect genetic associations was increased by restricting cases to those born in high-risk months. Analysis of data from the ICCSS revealed that restricting cases to high-risk birth months increased the evidence for association for three of six markers tested, two of which were associated with the gene FBXL21. Conclusions: Birth in the months of March, April, or May appears to be associated with elevated risk for schizophrenia in the ISHDSF. In attempting to find susceptibility loci for schizophrenia, restricting genetic association analyses to schizophrenics born in high-risk months may result in increased power to detect genetic association in some circumstances.

Epidemiological data on a wide range of mental disorders from community studies conducted in European countries are presented to determine the availability and consistency of prevalence, disability and treatment findings for the EU. Using a stepwise multimethod approach, 27 eligible studies with quite variable designs and methods including over 150,000 subjects from 16 European countries were identified. Prevalence: On the basis of meta-analytic techniques as well as on reanalyses of selected data sets, it is estimated that about 27% (equals 82.7 million; 95% CI: 78.5–87.1) of the adult EU population, 18–65 of age, is or has been affected by at least one mental disorder in the past 12 months. Taking into account the considerable degree of comorbidity (about one third had more than one disorder), the most frequent disorders are anxiety disorders, depressive, somatoform and substance dependence disorders. When taking into account design, sampling and other methodological differences between studies, little evidence seems to exist for considerable cultural or country variation. Disability and treatment: despite very divergent and fairly crude assessment strategies, the available data consistently demonstrate (a) an association of all mental disorders with a considerable disability burden in terms of number of work days lost (WLD) and (b) generally low utilization and treatment rates. Only 26% of all cases had any consultation with professional health care services, a finding suggesting a considerable degree of unmet need. The paper highlights considerable future research needs for coordinated EU studies across all disorders and age groups. As prevalence estimates could not simply be equated with defined treatment needs, such studies should determine the degree of met and unmet needs for services by taking into account severity, disability and comorbidity. These needs are most pronounced for the new EU member states as well as more generally for adolescent and older populations.

Schizophrenia is an illness causing impairment in thinking and functioning in many realms of everyday life. It is considered one of the most disabling of mental illnesses. This thesis considers the impact of schizophrenia in Ontario, including elevated mortality, degree of disability, economic impact. Some known risk factors for schizophrenia are increasingly common in Ontario, such as urban exposure, and a history of immigration. The impact of the illness in Ontario makes schizophrenia a good candidate for surveillance and case registry in this province. This thesis reviews the required elements of a surveillance system, including case definition and potential data sources and applies them to surveillance of schizophrenia in Ontario. The thesis then proposes a surveillance system and linked case registry based on combined OHIP, discharge abstract and mental health care administrative data, and outlines the necessary steps in implementation and evaluation of the system.

Epidemiological data on a wide range of mental disorders from community studies conducted in European countries are presented to determine the availability and consistency of prevalence, disability and treatment findings for the EU. Using a stepwise multimethod approach, 27 eligible studies with quite variable designs and methods including over 150,000 subjects from 16 European countries were identified. Prevalence: On the basis of meta-analytic techniques as well as on reanalyses of selected data sets, it is estimated that about 27% (equals 82.7 million; 95% CI: 78.5–87.1) of the adult EU population, 18–65 of age, is or has been affected by at least one mental disorder in the past 12 months. Taking into account the considerable degree of comorbidity (about one third had more than one disorder), the most frequent disorders are anxiety disorders, depressive, somatoform and substance dependence disorders. When taking into account design, sampling and other methodological differences between studies, little evidence seems to exist for considerable cultural or country variation. Disability and treatment: despite very divergent and fairly crude assessment strategies, the available data consistently demonstrate (a) an association of all mental disorders with a considerable disability burden in terms of number of work days lost (WLD) and (b) generally low utilization and treatment rates. Only 26% of all cases had any consultation with professional health care services, a finding suggesting a considerable degree of unmet need. The paper highlights considerable future research needs for coordinated EU studies across all disorders and age groups. As prevalence estimates could not simply be equated with defined treatment needs, such studies should determine the degree of met and unmet needs for services by taking into account severity, disability and comorbidity. These needs are most pronounced for the new EU member states as well as more generally for adolescent and older populations.

This thesis is based on two independent studies, the first in Stockholm County (index year 1984; n=302), and the second, a replication and validation study, in Uppsala County (index year 1991; n=455).

The general aim was to study all individuals with Long-term Functional Psychosis (LFP) within the two counties of Sweden from an epidemiological perspective and to perform specific studies on a subgroup of individuals with schizophrenia. In the Stockholm study, the total one-year LFP prevalence was 5.3/1 000; in the the rural, suburban and urban areas it was 3.4, 5.6 and 6.6/1 000, respectively. The total one-year prevalence of LFP in Uppsala was 7.3/1 000; in the rural, peripheral city and central city areas it was 6.0, 7.0, and 8.7/1 000, respectively.

Within the non-schizophrenic subpopulation, a pronounced difference was demonstrated between the two studies with substantially higher prevalence rates in the Uppsala study. The schizophrenic subgroup in Uppsala was re-diagnosed using parallel diagnostic systems (DSM-III, DSM-III-R, DSM-IV and ICD-10), and reasonably comparable prevalence estimates were obtained.

In both studies antipsychotic drugs were most frequently prescribed for the patients with schizophrenia, and the doses were considered as low to moderate. In the Uppsala study the doses of antipsychotic drugs decreased with a longer duration of illness, while the opposite was found in the Stockholm study.

The increased mortality rate among patients with schizophrenia was mainly due to unnatural causes of death and cardiovascular diseases, particularly among males.

The main methodological differences between the two studies were in the sampling procedures. In the Uppsala study, a larger number of care facilities were screened, and a broader set of diagnostic criteria were used for identifying cases from different registers.

Abstract The aim of this dissertation was to study outcomes in schizophrenia and their predictors in a meta-analysis and in the Northern Finland Birth Cohort 1966 (NFBC 1966). The NFBC 1966 is an unselected, population-based cohort consisting of 12,068 pregnant women and their 12,058 live-born children. This dissertation utilises data that has been collected from medical records, national registers and from two extensive psychiatric studies conducted when the cohort members were 34 and 43 years old, including interview, neurocognitive and brain magnetic resonance imaging data, and questionnaires. Depending on the topic investigated, the sample size ranges between 43 and 103 individuals with schizophrenia. The meta-analysis found that approximately 13.5% of subjects with schizophrenia recovered both clinically and socially, and the recovery rate has not increased in recent decades. Studies from countries with poorer economic indices had higher recovery estimates. In the NFBC 1966, individuals with schizophrenia who were young and single at illness onset, who experienced an insidious onset, and who had more hospital treatment days early on, were at greater risk of a poor outcome in terms of later psychiatric hospitalisations and lack of remission. A novel finding was an association between suicidal ideations at onset and higher number of later psychiatric hospitalisations. Associations were detected between decreased gray matter density in the left frontal and limbic areas and decreased total white matter volume, and concurrent poor outcomes at 34 years. Concerning neurocognitive functioning at 34 years, better long-term verbal memory predicted a better global outcome (symptoms, hospital treatments, social relationships and working combined) and better visual memory predicted a better vocational outcome nine years later. The results of this study show that recovery is possible, but not very common in schizophrenia. Though outcomes are relatively difficult to predict, many clinically relevant predictors were observed that can be used in predicting outcome in a nearly 20-year follow-up. However, more research is needed in order to explore predictors that could possibly be modified via early interventions so as to enhance outcomes
Tiivistelmä Tämän väitöstutkimuksen tarkoituksena oli tutkia skitsofrenian ennustetta ja ennustetekijöitä meta-analyysin ja Pohjois-Suomen vuoden 1966 syntymäkohortin avulla. Pohjois-Suomen vuoden 1966 syntymäkohortti on valikoitumaton, yleisväestöpohjainen kohortti, johon kuuluu 12 068 raskaana olevaa naista ja heidän 12 058 elävänä syntynyttä lastaan. Tässä väitöstutkimuksessa hyödynnetiin sairauskertomuksia, kansallisia rekistereitä sekä kahdessa laajassa kenttätutkimuksessa (34- ja 43-vuotistutkimukset) kerättyjä tietoja, jotka koostuvat haastatteluista, useista kyselyistä, neuropsykologisesta tutkimuksesta sekä aivojen magneettikuvauksesta. Tutkimuksen aiheesta riippuen aineiston koko eri osajulkaisuissa vaihteli 43:n ja 103:n välillä. Meta-analyysin perusteella 13,5 % skitsofreniaa sairastavista toipuu sekä kliinisesti että sosiaalisesti, eikä toipuminen ole viime vuosikymmeninä yleistynyt. Toipuneiden osuus oli suurempi köyhissä maissa. Pohjois-Suomen vuoden 1966 syntymäkohorttitutkimuksissa todettiin, että huonompi ennuste myöhempien sairaalahoitojen ja remission suhteen oli niillä, jotka olivat sairastuessaan nuoria ja naimattomia, joiden psykoosisairaus alkoi hitaasti ja joilla oli sairauden alkuvaiheissa enemmän sairaalahoitoja. Uusi löydös oli yhteys itsetuhoisten ajatusten ja myöhempien sairaalahoitojen välillä. Tiettyjen aivoalueiden tilavuuden ja rakenteen muutokset liittyivät monella tavoin samanhetkiseen taudinkuvaan 34-vuotiaana. Neurokognitiivisessa testauksessa parempi viivästetty kielellinen muisti 34-vuotiaana ennusti parempaa kokonaisvaltaista vointia (oireet, sairaalahoidot, sosiaaliset suhteet ja työssäkäynti yhdistettynä) ja parempi näönvarainen muisti ennusti työssäoloa 9 vuoden seurannassa. Tämän väitöstutkimuksen tulokset osoittavat, että skitsofreniasta toipuminen on mahdollista, vaikkakaan ei kovin yleistä. Vaikka taudinkulun ennustaminen on haastavaa, tutkimuksessa havaittiin useita kliinisesti merkittäviä tekijöitä, joilla on ennustearvoa jopa 20 vuoden seurannassa. Lisätutkimuksia kuitenkin tarvitaan, jotta löydettäisiin sellaisia ennustetekijöitä, joihin kohdistuvalla varhaisella interventiolla voitaisiin parantaa skitsofrenian ennustetta

Over the past few decades, epidemiological evidence has accrued to establish variance in psychosis risk across both geographical locations and demographic characteristics such as the excess risk in migrants and their descendants. Yet, the causes of this variation in rates between places and ethnic groups are still unclear, and I aimed to address this in this thesis. I conducted a systematic review and meta-analyses to synthesise existing literature on psychosis incidence in the six countries included in the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI) study: England, The Netherlands, Spain, France, Italy and Brazil. I subsequently analysed data from two parts of the EU-GEI study: a 17-centre service-based incidence study of psychosis, and a case-control arm utilising community volunteers. In the latter, I aimed to explain excess risk in ethnic and religious minorities using a theoretical sociocultural distance model I developed using literature from the social sciences. Here, I proposed that culturally distant minorities were particularly at risk of social exclusion, and this outsider experience led to increased psychosocial disempowerment (a lack of control over one’s life), which increased psychosis risk. I also explored if this model could explain any excess risk in those with increased genetic African ancestry in England. Incidence varied substantially between the studies included in the systematic review, although methodological differences could not be excluded as an explanation. The EU-GEI incidence study confirmed substantial variation by place, and demonstrated a higher incidence in ethnic minorities and for young men, as well as in areas characterised by a low percentage of owner-occupied housing. The sociocultural distance model could explain most of the excess psychosis risk in ethnic minorities, although some excess risk remained, particularly in the Black ethnic group. Social and cultural distance appeared to be more important predictors than psychosocial disempowerment, suggesting that chronic social injustices rather than acute stress play an important role. This model did not explain excess risk in religious minorities: those following any religion retained an excess risk. It could explain the excess risk in those with increased genetic African ancestry, although this was a small, exploratory sample and this will need replicating in larger studies. This thesis demonstrated, for the first time, that excess risk in ethnic minorities could be explained by the sociocultural distance model. Overall, the findings from this thesis confirm substantial variation in psychosis risk by person and place, and suggest that the social reality of the environment plays a crucial role in explaining this.

A prevalência de dor crônica entre pacientes com transtornos psiquiátricos é, possivelmente, no mínimo igual à da população geral; no entanto, são poucos os estudos na área. Objetivos: Avaliar a prevalência e as características da dor crônica em pacientes com esquizofrenia e comparar a qualidade de vida dos pacientes com e sem dor crônica. Método: Estudo transversal que envolveu uma amostra probabilística de 205 pacientes adultos, com diagnóstico de esquizofrenia (idade média 37 anos; 65% homens; média de anos de escolaridade 9 anos; 87% sem companheiro(a); 65% residiam com os pais; como ocupação principal, 25% eram trabalhadores dos serviços), atendidos em um ambulatório de hospital público do município de São Paulo, Brasil. Os pacientes foram entrevistados por meio de dois instrumentos caracterização da população e da dor e a Escala de Qualidade de Vida WHOQOL-bref. Resultados: A prevalência de dor em pacientes esquizofrênicos foi de 36,6% (75 pacientes). A dor foi mais presente no abdômen (30,7%), seguida da cabeça, face e boca (24%) e região lombar, sacra e cóccix (14,7%). Com relação à freqüência, 24% dos entrevistados referiram ter dor todos os dias, com duração entre 1 a 6 horas, 33,3% afirmaram ter dor de duas a três vezes por semana e 40% referiram dor em períodos mais espaçados, uma vez por semana e a cada quinze dias e somente 2,7% (n=2) uma vez por mês. O tempo médio de dor foi de 41 meses (DP=42,8). Dor moderada foi prevalente. Os escores de qualidade de vida foram baixos para os doentes do grupo sem dor (domínios físico 12,5; psicológico 11,9; social 7,4 e meio-ambiente 9,6) e com dor (domínios físico 11,4; psicológico 11,9; social 7,5 e meio-ambiente 10,6). Na comparação entre os grupos, o domínio físico apresentou diferença (p<0,001), o que indicou que pacientes esquizofrênicos com dor têm pior qualidade de vida por maior prejuízo funcional. Não houve diferença nos demais domínios (psicológico, relações sociais e meio-ambiente). Conclusão: O estudo é inédito em nosso meio e, em alguns aspectos, em âmbito internacional. A prevalência de dor crônica em pacientes esquizofrênicos foi semelhante à da população geral e o quadro álgico foi significativo em termos de tempo de duração, intensidade e freqüência dos episódios dolorosos. A qualidade de vida foi inferior à descrita em outros estudos, com pacientes esquizofrênicos, e a dor crônica piorou a qualidade de vida. Maior atenção à qualidade de vida de pacientes esquizofrênicos e ao controle da dor crônica deve ser observada
Background The prevalence of chronic pain among patients with psychiatric disturbance is possibly at least similar to the general population; however, there are too few studies in this field. Aims: to assess the chronic pain prevalence and its characteristics in schizophrenic patients, and to compare the quality of life of patients with and without chronic pain. Methods: Crossover study with a probabilistic sample of 205 adult outpatients with diagnosis of schizophrenia (mean age = 37 years, 65% men, mean scholarity = 9 years, 87% single, 65% living with parents, 25% had a job), treated in a governmental hospital of Sao Paulo city, Brazil. Patients were assessed by two instruments: characteristics of population/psychiatric disorder/pain and World Health Organization Quality of Life instrument (WHOQOL BREF). Results: Prevalence of pain in schizophrenic patients was 36,6%, (75 patients). Pain was more referred on abdomen (30.7%), followed by head/face/mouth (24%), and lumbar/sacral and coccyx regions (14.7%). Regarding frequency, 24% of the interviewees referred pain everyday with duration of 1 to 6 hours , 33.3% had pain two to three times a week, 40% referred pain with long intervals in between (once a week and each fortnight), and 2.7% (2 patients) once a month. Mean pain duration was 41 months (DP=42.8). Moderate pain was prevalent. Quality of life scores were low for patients without pain (domains 12,5; 11,9; 7,4;9,6) and with pain (domains 11,4; 11,9; 7,5; 10,6). In the comparison between groups, physical domain showed difference (P<0.001), which indicated that schizophrenic patients with pain have worse quality of life due to higher functional disability. There was no difference in other domains. Conclusion: This is a national original study, and in some aspects also original in the international scope. The prevalence of chronic pain in schizophrenic patients was similar to the general population and pain was significant in terms of duration, intensity and frequency. Quality of life was inferior to that described in other studies with schizophrenic patients and chronic pain worsened the quality of life. Higher attention to quality of life of schizophrenic patients and to the chronic pain control must be observed

The general construct of human cognition implies a series of mental processes by means of which human interpret and consequently act on the world that surrounds them (Sternberg y Mio, 2009). During the last decades, the recognition of human diversity and psychological variability among individuals has encouraged challenging questions addressing inter-individual differences that make each subject unique in terms of their cognitive performance (Baddeley, 2003; Botvinick, 2008). In particular, quantitative genetic studies show that both genetic variability and environmental factors are involved in the phenotypic expression of cognitive functions (Plomin, 2011). However, the mechanisms by which genes and exposure to environmental influences may contribute to the observed variability are not yet clear. The study of the origins of inter-individual differences in cognition is strongly associated with the ontogenic development of the human brain (Tau, 2010). As a consequence, cognitive alterations are considered a central trait in those mental disorders where neurodevelopmental alterations are assumed to exist, such as schizophrenia. This disease, which affects around 1% of the world’s population, is one of the main causes of years lost due to disability (WHO, 2004), while cognitive alterations in these patients explain about 20%-60% of the variance in measures of outcome (Green, 2004). The aetiological model of neurodevelopment in schizophrenia proposes that this disease might be the expression of neurobiological compromise that could begin early in the lifespan, even before the onset of the clinical symptoms (van Os, 2009). However, and despite the scientific efforts invested in the elucidation of its aetiological underpinnings, the heterogeneous presentation of the disease has prevented a deeper comprehension of these mechanisms. Are all cognitive domains heritable? Are there long-term consequences on cognition for the early exposure to environmental impact? What is the association between genetic variability and cognitive vulnerability? Can we identify specific neurobiological pathways in the expression of the cognitive alterations of patients with schizophrenia? These questions are explored in the present thesis through the analyses of twins- and family-based samples, which constitute powerful designs to study the effects of genetic and environmental variability on human cognition. In the six chapters of results that are the body of this thesis, complex models are proposed that aim at representing the mechanisms involved in the origin of cognitive variability at the population level. The findings included indicate that this variability could be the result of the relative contribution of genetic determination and environmental modelling, which could vary in different cognitive functions following ontogenic mechanisms of neurodevelopment. Specifically, results are reported on the influences of childhood maltreatment and socioeconomic status as environmental stressors, as well as Val158Met functional polymorphism of COMT gene as a genetic factor. The aetiological implications of the study of these processes are extended to the field of mental disorders, as the results may indicate that the cognitive variability present among patients with schizophrenia could support a model of developmental compromise in this disease. Accordingly, the effects of genetic and environmental influences on behaviour may underlie the heterogeneous expression of this highly disabling mental disorder. To sum up, the phenotypic diversity of schizophrenia and human cognition, far from representing an obstacle, lays the foundations for complex models of these traits that may feed an increasing understanding of their aetiology (Belsky, 2011). These findings highlight the putative role of neurobiological liability traits in crucial aspects of clinical practice. Risk factors might be identified that could be included as potential guidelines in the assessment and management of need-adapted treatments (Leiftker, 2009). Moreover, liability traits might operate as markers in preventive interventions for targeting individuals at risk of developing particular forms of the disease (Keshavan, 2011).
El constructo general de cognición humana involucra una serie de procesos mentales por medio de los cuales los individuos perciben, interpretan y, en consecuencia, actúan sobre la realidad que los rodea y sobre sus pares (Sternberg y Mio, 2009). En los últimos años, el reconocimiento de la diversidad humana y la variabilidad de los rasgos psicológicos entre los individuos ha promovido preguntas acerca de las diferencias inter-individuales que hacen a cada sujeto único en términos de cognición (Baddeley, 2003; Botvinick, 2008). En particular, los estudios de genética cuantitativa demuestran que tanto la variabilidad genética como los factores ambientales podrían estar involucrados en la expresión fenotípica de las funciones cognitivas (Plomin, 2011). Sin embargo, aún no son claros los mecanismos específicos por medio de los cuales los genes y el ambiente contribuyen a esta variabilidad. Las alteraciones cognitivas son un rasgo central en enfermedades mentales donde se presume que existen alteraciones del neurodesarrollo, como lo es la esquizofrenia. El modelo etiológico del neurodesarrollo de la esquizofrenia propone que esta enfermedad se expresaría como consecuencia de alteraciones neurobiológicas que iniciarían en una época temprana de la vida, incluso antes del desencadenamiento de los síntomas clínicos (van Os, 2009). No obstante, la presentación heterogénea de la enfermedad ha dificultado una comprensión más clara de los mecanismos involucrados en su manifestación. ¿Son todas las funciones cognitivas igualmente heredables? ¿Tienen los factores ambientales tempranos consecuencias a largo plazo sobre la cognición? ¿Cuál es la relación entre variabilidad genética y vulnerabilidad cognitiva? ¿Existen vías neurobiológicas específicas para la manifestación de las alteraciones cognitivas en pacientes con esquizofrenia? Estas preguntas se exploran en la presente tesis a partir de análisis basados en muestras de gemelos y en grupos familiares, que constituyen una manera metodológicamente potente de estudiar los efectos de la variabilidad genética y ambiental sobre la cognición humana. En este sentido, la diversidad fenotípica de la esquizofrenia y la cognición humana, lejos de representar un obstáculo para la investigación de su etiología, sienta las bases de modelos complejos que podrían fomentar una comprensión cada vez más completa de los mecanismos de vulnerabilidad y resiliencia posiblemente involucrados en su origen (Belsky, 2011).

La esquizofrenia está considerada un síndrome clínico heterogéneo con una etiopatogenia de origen multifactorial, en el que se incluyen factores ambientales, caracteriales y genéticos. A pesar de que más del 50% de la variabilidad de la enfermedad se puede deber a uno o varios factores genéticos, sólo un número limitado de variantes de riesgo genético y con un efecto muy débil han podido ser identificados. Muchos de ellos no han podido reproducirse tanto por la diversidad de las muestras y poblaciones estudiadas como por su asociación a diversas enfermedades mentales. Parte de esta heterogeneidad ha intentado ser solventada mediante el uso de endofenotipos o fenotipos intermedios y marcadores biológicos, usados como marcadores de vulnerabilidad genética. El gen de la Catecol-O-Metil Transferasa (COMT), que codifica un enzima catabolizador de dopamina en el córtex prefrontal ha sido estudiado como uno de los genes candidatos más prometedores en el estudio de la etiopatogenia de la esquizofrenia, especialmente el polimorfismo rs4680 (COMT Val158Met). La posibilidad de asociar alteraciones en la regulación dopaminérgica prefrontal se encontraría refrendada por la hipótesis dopaminérgica revisada, según la cual, en la esquizofrenia existiría un desequilibrio dopaminérgico, con un incremento en la función dopaminérgica subcortical D2 y un déficit de estimulación D1 cortical. El polimorfismo COMT Val158Met no ha podido confirmar su asociación con esquizofrenia, existiendo en todo caso un riesgo muy débil asociado al alelo hiperfuncionante Val158. El estudio de endofenotipos y marcadores biológicos ha sugerido la asociación del polimorfismo con alteraciones cognitivas, neurofisiológicas, neuroanatómicas y a fenotipos clínicos como agresividad, suicidio, síntomas psicóticos, edad de inicio y respuesta clínica, encontrándose resultados heterogéneos, así como la existencia de una modulación del riesgo de asociación por el consumo de cannabis. Gran parte de la heterogeneidad puede explicarse por problemas metodológicos, relacionados con la validez y representatividad de las muestras, que podrían solventarse con la recogida sistemática de variables en muestras epidemiológicas en fases iniciales de la enfermedad. Partiendo de la hipótesis de la existencia de una alteración dopaminérgica prefrontal en la esquizofenia, el alelo Val158 del gen COMT estaría asociado a una expresión de síntomas psicóticos más graves, especialmente los negativos y a factores de mal pronóstico. Igualmente el consumo de cannabis podría modular este riesgo, incrementando el riesgo o contrarrestando los factores protectores. El objetivo principal fue estudiar la asociación de la presentación clínica y evolución a las seis semanas de tratamiento antipsicótico de pacientes con un primer episodio de psicosis y las variantes del polimorfismo COMT Val158Met así como su interacción con el consumo de cánnabis premórbido. Los objetivos secundarios fueron estudiar la incidencia de esquizofrenia y validar la representatividad de la muestra, analizar la relación entre el polimorfismo Val158Met y sintomatología clínica, edad de inicio, respuesta al tratamiento y estimar la presencia de interacciones gen-ambiente con el consumo de cánnabis premórbido. Para ello, se reclutaron 174 pacientes consecutivos con un primer episodio de psicosis de esquizofrenia, trastorno esquizofreniforme, trastorno esquizoafectivo, trastorno psicótico breve o trastorno psicótico no especificado, incluidos dentro del programa PAFIP, diseñado para la detección y tratamiento de los casos incidentes en la comunidad de Cantabria de Febrero 2001 a Febrero 2005. Los pacientes fueron evaluados con una entrevista semiestructurada, las escalas SANS, SAPS, HDRS, CDS, YMRS y la entrevista SCID-I. Fueron seguidos durante las primeras seis semanas de tratamiento antipsicótico de asignación aleatoria (olanzapina, risperidona o haloperidol). El genotipo del polimorfismo rs4680 se determinó en muestras de sangre venosa. Un primer estudio mostró una incidencia tratada de 1.38/10000 y la asociación de esta incidencia a factores de riesgo como edad menor de 25 años, sexo masculino, estado marital soltero, desempleo nivel educativo primario, ambiente urbano y consumo de cannabis. Un segundo estudio encontró una asociación del alelo Val158 con sintomatología negativa al inicio y edad de inicio temprana, diagnóstico de esquizofrenia y duración de psicosis sin tratar prolongada en mujeres. En un tercer estudio se mostró la asociación del consumo de cánnabis premórbido con edad de inicio más temprana y una interacción entre consumo de cannabis y el genotipo, de modo que el consumo de cannabis contrarresta el efecto protector del alelo 158 Met. Finalmente, en un cuarto estudio se confirmó la persistencia de la asociación del genotipo Val158Met con mayor sintomatología negativa tras seis semanas de tratamiento, no encontrando diferencias en cuanto a la respuesta clínica. Los resultados muestran que el polimorfismo COMT Val158Met pueden estar asociados a una edad de inicio más temprana y una mayor gravedad de síntomas negativos. Del mismo modo, el consumo de cánnabis premórbido se asocia a una menor edad de inicio y se encuentra un patrón de interacción con el polimorfismo, eliminando los efectos protectores del alelo Met158. Los hallazgos sugieren la importancia del polimorfismo COMT Val158Met y del consumo de cannabis en la etiopatogenia de la esquizofrenia, que podría explicarse por la disminución de trasmisión dopaminérgica prefrontal.
The schizophrenia is considered a heterogeneous syndrome which has multifactorial causes, including environmental, characterial and genetic factors. Despite the fact that 50% of the variability of the illness is explained by genetic factors, only a limited number of genetic variants have been identified as weak risk factors. Most of them have not been replicated because of the heterogeneity of the studied samples and the association with other mental illnesses. This variability has been tried to be solved by the use of endophenotypes and biological markers, as indicators of genetic vulnerability. Catechol-O-Methyltransferase gene, that codifies a dopamine degradation enzyme active in prefrontal cortex, has been studied as one of the most promising candidates in the etiopathogenesis of schizophrenia, particularly the rs4860 polymorphism (Val158Met). The possible association with an altered prefrontal dopaminergic transmission would be supported by the revised dopaminergic theory. Following this theory, there is a dopaminergic disequilibrium in schizophrenia, with an increase in subcortical D2 dopaminergic transmission and a deficit in D1 cortical stimulation. COMT Val158Met polymorphism has not consistently associated with schizophrenia. The study of endophenotypes and biological markers has suggested associations with cognitive deficits, neurophysiologic and neuroanatomic markers and with clinical phenotypes, such as aggressiveness, suicide, psychotic symptoms, age of onset and clinical response. It also has been reported an interaction with cannabis in the modulation of the risk of psychosis. This heterogeneity could be explained by methodological biases, related to the validity and representativeness of the studied samples and may be solved with the systematic study of epidemiological samples of patients in the initial phases of psychosis. Following the hypothesis of the existence of an altered prefrontal dopaminergic transmission, the Val158 allele in the COMT gene would be associated with more severe psychotic symptoms, particularly negative symptoms and with poor prognostic factors. Likewise, the premorbid use of cannabis could modulate this risk, increasing the risk or counteract the protective factors. The main objective was to study the association between the clinical onset and evolution in the first 6 weeks of treatment and the COMT Val158Met polymorphism as well as the interaction with premorbid cannabis use. The secondary objectives were to study the incidence of schizophrenia and validate the representativeness of the sample, to analyse the relation between the Val158Met polymorphism and clinical symptoms, age of onset, clinical response to treatment and to estimate the presence of gen-environment interactions with the premorbid cannabis use. 174 consecutive first episode psychosis patients with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic disorder or psychosis non-otherwise specified were included in the PAFIP program. The program was designed for the detection and treatment of all cases in the region of Cantabria, form February 2001 to February 2005. The patients were assessed with a semi-structured interview, SANS, SAPS, HDRS, CDS, YMRS scales and the SCID-I interview. They were followed up to 6 weeks and treated with a randomly assigned antipsychotic (olanzapine, risperidone or haloperidol). Rs4680 polymorphism was assessed in peripheric blood samples. A first study showed a treated incidence of 1.38/10000 and the association with several risk factors such as age under 25 years, male gender, single marital status, unemployment, primary educational level, urban environment and cannabis use. A second study found an association between the Val158 allele and negative symptoms severity at onset, early age of onset, schizophrenia diagnosis and longer duration of untreated psychosis in females. A third study showed an association between premorbid cannabis use and early age of onset and an interaction between cannabis use and genotype, indicating that the cannabis use counter act the protective effect of the Met158Met allele in age of onset. Finally, in a fourth study the association between the Val158 allele and negative symptoms was confirmed after 6 weeks of treatment, although no relation was found with clinical response. The results showed that the COMT Val158Met polymorphism could be associated with an earlier age of onset and a higher severity of negative symptoms. Likewise, the premorbid use of cannabis was associated with an earlier age of onset and there was found a gene-environmental interaction, deleting the protective effect of the Met158 Allele. These findings suggest the importance of COMT Val158Met polymorphism and premorbid cannabis use in the etiopathogenesis of the schizophrenia that could be explained by a decrease in the prefrontal dopaminergic transmission.

Contexte : La schizophrénie est une pathologie qui concerne 1 % de la population mondiale. Les patients schizophrènes (PS) sont exposés à une surmortalité, à une surmorbidité. La mauvaise santé bucco-dentaire est souvent constatée par les soignants et les accompagnants. L’objectif de notre recherche est d’explorer les déterminants, les représentations et les perceptions de la santé orale des PS en Côte d’Or et de construire une échelle de qualité de santé orale spécifique à ces patients.Méthode : Un échantillon représentatif de 109 PS, tirés au sort en Côte d’Or, a permis d’explorer les déterminants sociodémographiques, dentaires, médicaux, liés au style de vie et associés à la santé orale. Une évaluation des caractéristiques psychométriques de l’échelle GOHAI (Global Oral Health Assessement Index) a également été réalisée. Puis, une étude qualitative basée sur 20 entretiens semi-directifs individuels de PS et de 6 soignants. Suivi d’entretiens de deux groupes (4 patients et 4 soignants) a permis d’explorer la perception et les représentations de la santé orale des PS observés et l’élaboration de la stucture hypothétique d’une échelle spécifique de mesure de la qualité de santé orale des PS.Résultats : Parmi les 109 patients inclus, 61.5 % sont des hommes. L'âge moyen est de 46.8 ans ± 12 ans. La majorité (78 %) ont fait des études secondaires (SE) et 79.8 % bénéficiaient d’un suivi ambulatoire. La durée moyenne de la maladie (DMM) était de 17.9 ans ± 9.4 ans, et 55.5 % étaient polymédicamentés. L’indice dentaire CAO (carie, absente, obturée) moyen est de 16.6 ± 8.1. Il y avait une relation significative entre SE, les indices de santé oraux, médicaux, la polymédicamentation, le style de vie et la DMM. Concernant la validation psychométrique de la GOHAI, la cohérence interne était excellente (α de Cronbach de 0.82). Les coefficients de corrélation intraclasse pour la fiabilité test-retest n'étaient pas significativement différents (p> 0.05). La validité de construction soutenue par 3 facteurs représente 60.94 % de la variance observée. La validité prédictive et concurrente a été validée. L’étude qualitative a permis de recueillir 3245 verbatims, candidats pour élaborer la structure hypothétique d’une nouvelle échelle, la SOHP, Schizophrenia Oral Health Profil. Les sélections successives des items issues des critères de décision du groupe d’expert et d’une étude de faisabilité auprès de 30 patients ont abouti à une échelle composée de 43 items et d’un module additionnel de 11 items.Conclusion : Nous avons montré l’intrication des problèmes de santé mentale et physique, de la santé orale et générale et la validité de la GOHAI chez les PS. Ce travail doit être poursuivi pour étudier la validation psychométrique de l’échelle SOHP sur une large population
Background: Schizophrenia is a disease that affects 1 % of the world population. Persons with schizophrenia (PWS) are exposed to excess morbidity and mortality. Poor oral health among PWS is often observed by caregivers and accompanying persons. The objective of our study was to explore predictive factors, representations and perceptions of oral health among PWS and to construct a specific oral health quality of life scale for PWS.Methods: In a randomly selected, representative sample of 109 PWS in the Côte d’Or Department, we recorded socio-demographic, dental, and medical and lifestyle factors associated with oral health. An evaluation of the psychometric characteristics of the Global Oral Health Assessment Index (GOHAI) scale was also performed, as well as a qualitative study based on semi-directive interviews with 20 PWS and 6 carers. Two focus groups (4 patients and 4 carers) enabled investigation of the perceptions and representations of oral health among PWS and building the first draft prototype of a specific tool to assess oral health quality of life of PWS.Results: Among 109 patients included, 61.5% were male, and average age was 46.8 ± 12.0 years. The majority (78%) had secondary level education and 79.8% received ambulatory care. The mean duration of schizophrenia was 17.9 ± 9.4 years, and 55.5% were taking several medications. The average DMFT (Decayed, Missing, and Filled Teeth) was 16.6 ± 8.1. There was a significant relationship between level of education and oral health, lifestyle, medical conditions, polypharmacy and DMI. Concerning the psychometric validation of the GOHAI, internal consistency was excellent (Cronbach α = 0.82). The intraclass correlation coefficients for test-retest reliability were not significantly different (p> 0.05). Construct validity was supported by three factors which accounted for 60.94% of the variance observed. Predictive and concurrent validity were validated. The qualitative study yielded 3245 candidate verbatims for the development of a new scale, namely the SOHP, Schizophrenia Oral Health Perception Profile. Successive selections of items from the expert panel decision criteria and based on a feasibility study in 30 patients resulted in a scale comprising 43 items and one additional module of 11 items.Conclusion: We show the intricate links existing between mental and physical, oral and general health and the GOHAI validity in PWS. Further research is necessary to validate the psychometric properties of the SOHP scale in a larger population

Contexte : Les neuroleptiques sont souvent prescrits chez les sujets âgés et les patients souffrant de schizophrénie qui sont des personnes vulnérables. Notre objectif était d'étudier l'impact des NLP en situation réelle de prescription, dans ces deux populations. Etude 1. Consommation de neuroleptiques et décès en période de canicule chez les sujets âgés. A partir de données de l'Assurance Maladie, nous avons comparé les prescriptions de NLP chez des sujets âgés décédés pendant la canicule d'août 2003 (n=11624) aux prescriptions de témoins non décédés. Nous avons mis en évidence une association entre risque de décès et consommation de neuroleptiques, que ce soit juste avant ou pendant le pic de canicule et indépendamment d'autres médicaments, d'une démence ou d'une pathologie cardiaque. Etude 2. Efficacité réelle des NLP chez les patients souffrant de schizophrénie. A partir de données d'une cohorte observationnelle ayant inclus en France entière des schizophrènes adultes, nous avons montré que chez les patients déjà traités par NLP (n=5500), il y avait une association entre traitement par antipsychotique atypique (vs. NLP classique) et une meilleure satisfaction avec les soins et ce, pour tous les AA pris en compte et indépendamment du niveau de symptomatologie. Par ailleurs, chez les patients naïfs vis-à-vis de tout NLP et pour qui un traitement était introduit pour la première fois (n=467), un tiers des patients ne s'améliorait pas. Les facteurs prédictifs d'une meilleure réponse clinique étaient une moindre sévérité initiale globale des symptômes et des symptômes négatifs de schizophrénie. Au total, il existait cinq types de trajectoires d'évolution clinique.