The Origins of Schizophrenia

The Origins of Schizophrenia

Alan S. Brown
Paul H. Patterson
Copyright Date: 2012
Pages: 448
https://www.jstor.org/stable/10.7312/brow15124
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  • Book Info
    The Origins of Schizophrenia
    Book Description:

    The Origins of Schizophrenia synthesizes key findings on a devastating mental disorder that has been increasingly studied over the past decade. Advances in epidemiology, translational neuroscience technology, and molecular and statistical genetics have recast schizophrenia's neurobiological nature, identifying new putative environmental risk factors and candidate susceptibility genes. Providing the latest clinical and neuroscience research developments in a comprehensive volume, this collection by world-renowned investigators answers a pressing need for balanced, thorough information, while pointing to future directions in research and interdisciplinary collaboration.

    The book, featuring a foreword by Robert Freedman, M.D., thoroughly examines these topics from the vantage points of epidemiologic, clinical, and basic neuroscience approaches, making it an essential resource for researchers in psychiatry, psychology, and neuroscience and for clinical mental health professionals.

    eISBN: 978-0-231-52192-5
    Subjects: Psychology, Health Sciences

Table of Contents

  1. Front Matter
    (pp. i-vi)
  2. Table of Contents
    (pp. vii-x)
  3. FOREWORD
    (pp. xi-xii)
    Robert Freedman

    I know the editors of this important volume, Alan Brown and Paul Patterson, well enough to have a glimmer of insight into how they came together to lead this book. They are both tenacious iconoclasts who have doggedly championed the hypothesis of maternal infection as a risk factor for schizo phre nia while the rest of their peers were chasing dopamine and genes. The answer that they arrived at in de pen dently, Alan Brown from his tireless and creative work in epidemiology and Paul Patterson from his creative approaches in animal neurobiology, is quite striking because it was entirely...

  4. ACKNOWLEDGMENTS
    (pp. xiii-xvi)
  5. INTRODUCTION
    (pp. 1-2)
    ALAN S. BROWN and PAUL H. PATTERSON

    This book was motivated by recent evidence that the origins of schizophrenia almost certainly encompass both environmental and genetic factors, which, through both independent and interactive neurodevelopmental mechanisms, appear to play important roles in this disorder. This theory is based on support from several domains of research. First, many new findings on potential environmental etiologies have emerged from epidemiologic studies. These investigations feature fundamental methodologic improvements over prior work, including birth cohort and other longitudinal approaches, prospective and more precise definitions of exposure status, control of confounding, and addressing bias due to attrition. These developments have markedly improved the validity...

  6. OVERVIEW SCHIZOPHRENIA AND THE LIFETIME TRAJECTORY OF PSYCHOTIC ILLNESS: Developmental Neuroscience and Pathobiology, Redux
    (pp. 3-22)
    JOHN L. WADDINGTON, ROBIN J. HENNESSY, COLM M. P. O’TUATHAIGH, OLABISI OWOEYE and VINCENT RUSSELL

    Pathobiology of schizophrenia: There is now voluminous evidence from neuroimaging, neuropathologic, neurochemical, and neuropsychological studies for the existence of abnormalities of brain structure and function in schizophrenia. These likely reflect dysfunction in one or more neuronal networks that integrate activity across a number of regions to subserve fundamental psychological processes.

    Developmental origins: There is now a wealth of indirect, epidemiologic evidence and increasing “hard” biological evidence that schizophrenia involves disruption to brain development over early gestational life.

    The enigma of “progression”: Much current research focuses on whether schizophrenia shows progression—particularly in terms of the emergence of an active, morbid...

  7. PART 1 Clinical Research on Risk Factors for Schizophrenia
    • SECTION 1 Environmental Factors:: Epidemiologic Studies on the Etiologies of Schizophrenia
      • CHAPTER 1 MATERNAL INFECTION AND SCHIZOPHRENIA
        (pp. 25-57)
        ALAN S. BROWN

        Early studies of the connection between maternal infection and schizophrenia in offspring were limited by relatively imprecise definitions of exposure status.

        Recent studies have capitalized on the use of prospective documentation of exposure using maternal biomarkers of infection and longitudinal follow-up of offspring to provide more definitive evidence of associations between maternal infection and schizophrenia.

        The identification of maternal infectious exposures related to schizophrenia may facilitate the identification of susceptibility genes that interact with these exposures.

        If the findings are replicated, these studies have potentially important implications for prevention given that exposure to infection is relatively common during pregnancy and...

      • CHAPTER 2 PRENATAL NUTRITION AND THE ETIOLOGY OF SCHIZOPHRENIA
        (pp. 58-95)
        KRISTIN N. HARPER and ALAN S. BROWN

        Studies demonstrating a link between exposure to famine during gestation and elevated risk of developing schizophrenia have drawn attention to the role of prenatal nutrition in the development of this disorder.

        Malnutrition during pregnancy could increase schizophrenia risk through multiple pathways, such as elevated mutation rate, epigenetic alterations, or other types of physiologic changes.

        Epidemiologic associations between a number of prenatal nutrition measures and schizophrenia have been discovered, including low and high maternal body mass index (BMI), low and high birth weight, elevated levels of homocysteine, and low iron levels.

        The case for a biologically plausible role in influencing schizophrenia...

      • CHAPTER 3 OBSTETRIC COMPLICATIONS AND SCHIZOPHRENIA: Historical Overview and New Directions
        (pp. 96-119)
        MARY CLARKE, SARAH RODDY and MARY CANNON

        The field of obstetric complications has been intensively studied over the last five decades and has evolved over the years from using high-risk designs to case-control designs and finally to population-based studies.

        The population-based design has led to good evidence that there is a small but noteworthy association between obstetric complications and the later development of schizophrenia.

        There are several potential mechanisms that may mediate the relationship between obstetric complications and schizophrenia. There is also evidence that obstetric complications may have synergistic effects with other schizophrenia risk factors.

        Obstetric complications may play an important role in elucidating the etiology of...

      • CHAPTER 4 MATERNAL STRESS DURING PREGNANCY AND SCHIZOPHRENIA
        (pp. 120-139)
        MARY C. IAMPIETRO and LAUREN M. ELLMAN

        The maternal experience of stressful life events during pregnancy is associated with increased risk of schizophrenia in offspring.

        Maternal stress in pregnancy is related to an increased risk of obstetric complications that have been consistently linked with schizophrenia.

        Maternal stress during pregnancy is associated with childhood cognitive, social, and emotional disturbances that commonly occur during the premorbid period of schizophrenia.

        Evidence is accumulating that maternal emotional and psychosocial experiences during pregnancy can be communicated to the fetus and influence fetal development and subsequent neurodevelopmental sequelae in offspring. It has been repeatedly documented that mothers who experience certain stressful life events...

      • CHAPTER 5 ADVANCING PATERNAL AGE AND THE RISK FOR SCHIZOPHRENIA
        (pp. 140-155)
        SARAH CRYSTAL, KARINE KLEINHAUS, MARY PERRIN and DOLORES MALASPINA

        Epidemiologic evidence has established the relationship between advanced paternal age and schizophrenia.

        Animal models and epidemiologic research have described effects of paternal age on learning and cognition.

        Paternal age-related schizophrenia may be a variant of schizophrenia.

        Genetic mechanisms may underlie the relation between paternal age and schizophrenia.

        Epigenetics may partially explain the finding that advanced paternal age is associated with schizophrenia.

        An increasing risk of schizophrenia with advancing paternal age has been demonstrated through epidemiologic studies during the past decade. Before 2001, the results of research studying paternal age and schizophrenia were inconsistent with regard to risk of schizophrenia and...

      • CHAPTER 6 CANNABIS USE AS A COMPONENT CAUSE OF SCHIZOPHRENIA
        (pp. 156-172)
        PAOLA CASADIO, MARTA DI FORTI and ROBIN M. MURRAY

        Cannabis is the most popular illicit drug in the world. Epidemiologic studies have reported consistently that cannabis use is associated with later schizophrenia, even after controlling for several confounding factors. Those studies that collected data on the extent of cannabis use also reported a dose-response effect.

        Experimental studies confirm that administration of Δ9-tetrahydrocannabinol (Δ9-THC), the main psychoactive ingredient of cannabis, can induce psychosis.

        Only a minority of cannabis users develop psychosis. This can be explained in part by the amount and duration of the consumption of cannabis. Individual genetic vulnerability may also play a role.

        There exists a plausible biological...

    • SECTION 2 Genetics and Epigenetics
      • CHAPTER 7 SCHIZOPHRENIA GENETICS: What Have We Learned from Genomewide Association Studies?
        (pp. 175-209)
        ALAN R. SANDERS, JUBAO DUAN and PABLO V. GEJMAN

        Genomewide experiments are bringing about major conceptual changes in our understanding of the genetics of schizophrenia.

        Uncommon copy number variations (mainly deletions—see chapter 8, this book) and common single nucleotide polymorphism alleles have been reliably demonstrated to be associated with schizophrenia

        A polygenic model is plausible.

        Partial genetic overlap of schizophrenia with autism and with bipolar disorder is supported.

        The first family studies of schizophrenia were conducted in the early twentieth century, but only recently, myriad genomic, bioinformatic, and analytic tools have made possible an incipient understanding of the molecular genetics of schizophrenia We review here the status of...

      • CHAPTER 8 GENETIC ARCHITECTURE OF SCHIZOPHRENIA: The Contribution of Copy Number Variation
        (pp. 210-226)
        MARIA KARAYIORGOU, REBECCA J. LEVY and BIN XU

        Rare mutations are an integral component of the genetic architecture of schizophrenia and account for a large portion of the genetic heterogeneity of the disease.

        Copy number variants (CNVs, defined as deletions or duplications larger than 1 kb) are one of the most intriguing types of variation in the human genome, the extent of which was previously unappreciated.

        Rare CNVs are important components and sources of genetic heterogeneity in the etiology of schizophrenia.

        The 22q11.2 microdeletion is the prototype rare but recurrent schizophrenia-associated CNV and one of the best known genetic risk factors for schizophrenia.

        Schizophrenia-associated rare CNVs affect a...

      • CHAPTER 9 THE EPIGENETICS OF SCHIZOPHRENIA
        (pp. 227-252)
        IRIS CHEUNG, MIRA JAKOVCEVSKI and SCHAHRAM AKBARIAN

        DNA methylation—the methylation of cytosine residues almost exclusively at CpG dinucleotides—and posttranslational modifications of histone tails are important epigenetic mechanisms that affect gene expression in mammals.

        Inheritance of epigenetic states across generations has been observed in different plant and animal species. Evidence for this type of epigenetic inheritance in human diseases has been described in a small number of cases.

        Changes in expression in genes involved in various neuronal functions in postmortem tissues of schizophrenic patients have been described extensively.

        Whether these changes are contributed by epigenetic mechanisms is a major focus of current research in schizophrenia.

        A...

  8. PART 2 Preclinical Research on Etiologies of Schizophrenia
    • SECTION 1 Animal Models of Environmental Factors and Schizophrenia
      • CHAPTER 10 ANIMAL MODELS OF THE MATERNAL INFECTION RISK FACTOR FOR SCHIZOPHRENIA
        (pp. 255-281)
        PAUL H. PATTERSON

        Epidemiologic evidence highlights maternal infection as an important risk factor for schizophrenia in the offspring.

        Rodent models of viral and bacterial maternal infection yield offspring with a series of abnormal behaviors and neuropathology consistent with those found in schizophrenia. None of the behaviors or pathology is specific for schizophrenia, however.

        These models are being used to investigate the molecular and cellular pathways that mediate the effects of maternal infection on fetal brain development.

        Interventions during maternal immune activation (MIA) in utero, or even in adolescent offspring, demonstrate that the development of abnormal behavior and neuropathology can be prevented.

        Experiments with...

      • CHAPTER 11 DEVELOPMENTAL VITAMIN D DEFICIENCY AS A RISK FACTOR FOR SCHIZOPHRENIA
        (pp. 282-299)
        XIAOYING CUI, DARRYL W. EYLES, THOMAS H. J. BURNE and JOHN J. MCGRATH

        Developmental vitamin D deficiency is a candidate risk factor for schizophrenia.

        Over the last decade, evidence has accumulated demonstrating that vitamin D plays a role in brain development.

        The Developmental Vitamin D (DVD) deficiency rat model demonstrates a range of altered neurobiological features, some of which are consistent with features of schizophrenia.

        The DVD deficiency model confirms the biological plausibility of this exposure for schizophrenia, but further epidemiologic research is required in order to demonstrate a link to the disease.

        It is widely accepted that schizophrenia is a heterogeneous group of disorders influenced by a variety of genetic and environmental...

      • CHAPTER 12 ANIMAL MODELS OF PRENATAL PROTEIN MALNUTRITION RELEVANT FOR SCHIZOPHRENIA
        (pp. 300-334)
        LISA M. TARANTINO, TERESA M. REYES and ABRAHAM A. PALMER

        Protein malnutrition during development results in behavioral, structural, and neurochemical changes in adulthood that mimic many of the characteristics of psychiatric diseases, including schizophrenia.

        Animal models have been used extensively to study the effects of protein malnutrition during development.

        Animal models have been, and will continue to be, a valuable tool for elucidating the environmental, genetic, and epigentic consequences of protein malnutrition and its role in the development of schizophrenia and other psychiatric disorders.

        Exposure to a variety of environmental challenges in utero has been shown to elevate risk for schizophrenia and other psychiatric disorders; for reviews, see Weiss & Feldon...

      • CHAPTER 13 ANIMAL MODELS OF THE MATERNAL STRESS RISK FACTOR FOR SCHIZOPHRENIA
        (pp. 335-362)
        PAUL H. PATTERSON

        Epidemiologic evidence implicates maternal stress as a risk factor for schizophrenia in the offspring.

        In a variety of mammalian species, the offspring of stressed mothers display numerous altered behaviors, depending on the severity and type of the stress, its timing, and the gender of the offspring.

        Many of these behaviors are associated with disturbance of the hypothalamic-pituitary-adrenal axis and are found in human major depressive disorder and schizophrenia.

        Stress-induced elevation of maternal glucocorticoid levels is a major factor in altering fetal brain development, and the fetal brain and the placenta are targets of maternal hormone action.

        Pharmacological and environmental interventions...

    • SECTION 2 Animal Models of Genetic Factors and Schizophrenia
      • CHAPTER 14 DISC1: A New Paradigm for Schizophrenia and Biological Psychiatry
        (pp. 365-381)
        DAVID PORTEOUS

        The Disrupted-in-Schizophrenia gene (DISC1) is a causal genetic risk factor for schizophrenia and related psychiatric disorders.

        The DISC1 protein plays a key role in neurodevelopment and neurosignaling.

        The DISC1 pathway is a potential target for novel, knowledge-based interventions.

        St Clair and colleagues (1990) first reported a Scottish family with a high loading of psychiatric illness that cosegregated with a balanced translocation between chromosomes I and II (Log of the Odds [LOD]=3.4). In a major follow-up of family members and newly located relatives, Blackwood and colleagues (2001) reported on 87 family members, 37 of whom carried the translocation. Of 29 individuals...

      • CHAPTER 15 MUTANT MODELS OF Nrg1 AND ErbB4: Abnormalities of Brain Structures, Functions, and Behaviors Relevant to Schizophrenia
        (pp. 382-412)
        YACHI CHEN, LORNA W. ROLE and DAVID A. TALMAGE

        Multiple studies provide evidence that NRG1 and ERBB4 are candidate susceptibility genes for schizophrenia.

        Mice with genetic disruption in Nrg1 or ErbB4 display enlarged lateral ventricles and reduced spine density on hippocampal subicular dendrites, which are characteristics of schizophrenia neuropathology.

        Nrg1 and ErbB4 mutant mice also display hyperlocomotor activity, impaired sensorimotor gating, abnormal social interactions, and diminished performance in learning and memory tasks. These abnormalities are consistent with alterations in cortico–limbic functions that often are severely compromised in patients with schizophrenia.

        The neuregulin proteins (NRGs) represent a large family of growth factors encoded by four individual genes (NRGI-4). Of...

  9. List of Contributors
    (pp. 413-418)
  10. INDEX
    (pp. 419-428)