Early Disease Processes in Schizophrenia -
Research Questions
Lived experience research as a resource for recovery: a mixed methods study -
Lived experience research as a resource for recovery: a mixed methods study -
Lived experience research is conducted by people who have experience of mental health issues and is therefore better placed than more traditional research to illuminate participants’ experiences. Findings that focus on identifying enablers of recovery from a lived experience perspective have the potential to assist people in their recovery process. However, this lived experience research is often difficult to find, access and interpret. We coproduced user-friendly and engaging resources to disseminate findings from six lived experience research studies. This paper seeks to answer the research questions: a) Did exposure to lived experience research increase hopefulness for participants?; and b) How else did interacting with lived experience research resources influence participants’ lives?
Studies
Lived experience research as a resource for recovery: a mixed methods study
Lived experience research as a resource for recovery: a mixed methods study
Full Article
s12888-020-02861-0.pdf
Background
Lived experience research is conducted by people who have experience of mental health issues and is therefore better placed than more traditional research to illuminate participants’ experiences. Findings that focus on identifying enablers of recovery from a lived experience perspective have the potential to assist people in their recovery process. However, this lived experience research is often difficult to find, access and interpret. We coproduced user-friendly and engaging resources to disseminate findings from six lived experience research studies. This paper seeks to answer the research questions: a) Did exposure to lived experience research increase hopefulness for participants?; and b) How else did interacting with lived experience research resources influence participants’ lives?
Asphyxia and Scizophrenia - Aetiology
Asphyxia and Scizophrenia - Aetiology
Perinatal asphyxia (also known as neonatal asphyxia or birth asphyxia) is the medical condition resulting from deprivation of oxygen to a newborn infant that lasts long enough during the birth process to cause physical harm, usually to the brain. There is a strong association between signs of asphyxia at birth and schizophrenia. Signs of asphyxia at birth are associated with an increased risk of schizophrenia in adults
Studies
Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study
Signs of asphyxia at birth and risk of schizophrenia. Population-based case-control study
Journal Published
Br J Psychiatry. Nov;179:403-8
Year Published
2001
Full Article
signs_of_asphyxia_at_birth_and_risk_of_schizophrenia.pdf
Hypothesis
To assess the role of different complications, and in particular to distinguish between disordered foetal development and hypoxia at birth.
Background
- It has been suggested that foetal or neonatal damage to the central nervous system (CNS) could increase the risk of schizophrenia as an adult
- Schizophrenia is twice as likely in those with any obstetric complication.
- Previous research has found an association between obstetric complications and schizophrenia, but in many studies the sample size was limited, and no assessment of specific exposures was possible.
Autoimmune Diseases & Schizophrenia - Aetiology
Autoimmune Diseases & Schizophrenia - Aetiology
Studies
Autoimmune Diseases and Psychotic Disorders
Autoimmune Diseases and Psychotic Disorders
Journal Published
Frontiers in Psychiatry
Year Published
2019
Abstract
AutoimmuneZDiseasesZZPsychoticZDisorders.pdf
Background
- The association between immunological processes and mental disorders was observed by doctors centuries before the immune system was discovered.
- Psychosis arising either with the occurrence or disappearance of acute fever has been described by many scientists from Hippocrates around 400 BC to Kraepelin around 1900. In the 1930s it was first hypothesized by Hermann Lehmann-Facius that schizophrenia was the product of an autoimmune reaction with antibodies attacking brain tissue
- In the 1950s and 1960s it was noticed that celiac disease seemed to occur more often within those suffering from schizophrenia than in the general population, and conversely, that schizophrenia occurred less frequently within patients with rheumatoid arthritis.
- Additionally, autoantibodies cross-reacting with brain antigens were found in patients with schizophrenia back in the 1960s, and interest in anti-neuronal antibodies in psychotic disorders has increased during the last couple of decades, with an increasing number of reports on previously unknown antibodies with brain reactivity in patients suffering from psychosis.
- The amount of evidence supporting the notion of a link between immunological processes and psychotic disorders has increased.
- Elevated levels of inflammatory markers have been found both in the blood and CSF of patients with psychosis, with even higher levels in patients in first episode psychosis or acute relapse.
- Furthermore, some have found association between higher levels of inflammation in childhood and adolescence and increased risk of psychotic disorders, elevated inflammatory biomarkers has been associated with lack of treatment response, and anti-inflammatory treatment has been found to have especially beneficial effect in an inflamed subgroup of patients.
- Moreover, it has been suggested that schizophrenia could be an autoimmune disease, based on similarities such as the remitting-relapsing phenotype of the illness, as well as the above-mentioned immunological processes.
- Research in the field of psychoneuroimmunology is still evolving, with many different aspects being investigated.
- The notion of a role of the immune system in psychotic disorders seems evident, and understanding the link between autoimmune diseases and mental disorders may shed light on possible etiological mechanisms herein.
- Understanding how the immune system and psychotic illness interact can improve our understanding of psychosis and give rise to a wide range of new treatment options in psychiatry; amongst other the possibility to identify subgroups of patients with psychotic disorders and ongoing inflammatory processes that could benefit from more targeted treatment.
- Additionally, it is very important for clinicians to be aware of somatic comorbidities, particularly in patients with psychotic disorders, in order to improve detection and treatment, and thus the course of illness.
- The notion of immunological pathways playing a role in the etiology of a subset of psychotic disorders has received increased interest in the last decades.
- There is an apparent link between autoimmune diseases and psychotic disorders.
- This is supported by genetic findings associating immune-related genetic markers with schizophrenia and clinical studies finding increased levels of inflammatory markers in patients with psychosis.
- Several large-scale epidemiologic studies have found positive associations between autoimmune diseases and psychosis. Particularly, autoimmune diseases as multiple sclerosis and lupus are known to have higher frequencies of neuropsychiatric symptoms, including psychosis, compared to healthy controls.
- Cross sectional studies have found higher prevalence of psychiatric diagnoses among those with autoimmune diseases, and longitudinal studies have shown bidirectional associations between several autoimmune diseases and increased risks associated with schizophrenia.
- Moreover, a family history of autoimmune diseases has been shown to be associated with an increased risk of psychotic disorders and vice versa. In this review we will summarize the epidemiologic evidence on associations between autoimmune diseases seases and psychosis.
- Possible mechanisms accountable for the association will be discussed, amongst others the probable role of shared genetic risk factors, the impact of infections on both autoimmunity and the development of psychotic disorders, and the potential role of the microbiome.
Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.
Genome-Wide Association Studies Suggest Limited Immune Gene Enrichment in Schizophrenia Compared to 5 Autoimmune Diseases.
School, Department or Faculty
Schizophrenia Working Group of the Psychiatric Genomics Consortium
Journal Published
Schizophrenia Bulletin
Year Published
2016
Authors / Collaborators
Pouget JG1, Gonçalves VF2, Raychaudhuri S, Kennedy JL, Knight J5.
Hypothesis
The variation in immune genes contributes to schizophrenia
Background
- There has been intense debate over the immunological basis of schizophrenia, and the potential utility of adjunct immunotherapies.
- The major histocompatibility complex is consistently the most powerful region of association in genome-wide association studies (GWASs) of schizophrenia and has been interpreted as strong genetic evidence supporting the immune hypothesis.
- However, global pathway analyses provide inconsistent evidence of immune involvement in schizophrenia, and it remains unclear whether genetic data support an immune etiology per se.
Is schizophrenia an autoimmune disease? A review.
Is schizophrenia an autoimmune disease? A review.
Journal Published
Methods Find Exp Clin Pharmacol.
Year Published
1984
Authors / Collaborators
Knight JG.
Background
- Autoimmunity has been shown to be the basis of an ever-increasing number of human diseases.
- Schizophrenia shares a number of genetic features with these autoimmune diseases and therefore could be an autoimmune disease itself.
- Several lines of evidence suggest that overactivity of dopaminergic pathways in some areas of the brain are involved in schizophrenia, but the apparent absence of an increase in dopamine turnover suggests that this hyperactivity could be mediated by a dopamine agonist rather than by dopamine itself.
- Schizophrenia is reviewed in the light of precedents from the field of autoimmune diseases in which autoantibodies have been shown to be able to interact with, and sometimes stimulate hormone receptors, thereby causing disease.
The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia
The Autoimmune and Infectious Etiological Factors of a Subset of Schizophrenia
Journal Published
British Journal of Medical Practitioners
Year Published
2015
Authors / Collaborators
James Paul Pandarakalam
Abstract
TheZAutoimmuneZZInfectious.pdf
Hypothesis
The author has reported on a review of the literature relating to the immunity- and viral-based aetiological models of schizophrenia to gain a detailed understanding of aetiological models of a subset of schizophrenia.
Background
- A clearer understanding of the aetio-pathogenesis of schizophrenia would ultimately lead to effective treatment strategies and provide the impetus for elucidation.
- The autoimmune hypothesis promulgates that it is the auto-antibodies that are responsible for schizophrenia and, according to the viral hypothesis, it may be the body’s abnormal response to a slow viral infection or the undefeated viral antigens causing the schizophrenia pathology.
- The autoimmune and viral hypotheses are interlinked, as autoimmune disorders can be triggered by microbial infection.
- Viral aetiology is less convincing than the autoimmune model, but from a treatment perspective, the former is more promising than the latter.
A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis
A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis
Journal Published
Journal of Neuroinflammation
Year Published
2018
Authors / Collaborators
Souhel Najja , Johann Steiner , Amanda Najjar and Karl Bechter
Childhood Antecedents & Schizophrenia - Aetiology
Childhood Antecedents & Schizophrenia - Aetiology
-
Reaching milestones of motor development
-
Speech problems
-
Solitary play preferences at ages
-
Lower ratings of the mother's skills and understanding of the child
-
Subtle motor signs
-
Less likely to progress to high school, despite academic ability.[97])
-
Symptoms of schizophrenia often appear soon after puberty, when the brain is undergoing significant maturational changes
-
Disease process of schizophrenia begins prenatally, lies dormant until puberty, and then causes a period of neural degeneration that causes the symptoms to emerge.
-
Unusual motor coordination
-
Unusual movements
-
Interpersonal difficulties l
-
Neuromotor, receptive language and cognitive development.
-
Neurobehavioral deficits
-
A poorer family environment
-
Disruptive school behaviour
-
Poor peer engagement
-
Immaturity
-
Unpopularity
-
Poorer social competence
-
Childhood experiences of abuse or trauma
-
Hallucinations and other symptoms considered characteristic of schizophrenia and psychosis were at least as strongly related to neglect and childhood abuse as many other mental health problems.
Infections & Schizophrenia - Aetiology
Infections & Schizophrenia - Aetiology
Viral infections, in utero or in childhood, have been associated with an increased risk of later developing schizophrenia.
- Influenaza
- Polio
- Measles
- Varicella-zoster
- Rubella
- Herbes Simplex
- Maternal genital infections
- Borna Disease Virus
- Toxoplasma gondii
- The interaction of the developing fetus with pathogens such as viruses or antibodies
Obstetric Complications in Schizophrenia - Aetiology
Obstetric Complications in Schizophrenia - Aetiology
Studies
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review
Obstetric Complications and Schizophrenia: Historical and Meta-Analytic Review
Journal Published
Am J Psychiatry
Year Published
2002
Authors / Collaborators
Mary Cannon, Peter B. Jones, Robin M. Murray
Hypothesis
This paper reviews the literature on obstetric complications as a risk factor for schizophrenia. The authors trace the evolution of this literature through different methods and carry out a quantitative review of the results from prospective, population-based studies
Background
- The much-investigated association between obstetric complications and schizophrenia has provided crucial support for developmental and nongenetic etiological models of the disorder.
- The first mention of an association between birth complications and schizophrenia occurred in the American Journal of Psychiatry in 1934.
- Rosanoff and colleagues published “The Etiology of So-Called Schizophrenic Psychoses” based on detailed case reports of 142 pairs of twins concordant and discordant for schizophrenia.
- The authors concluded that schizophrenia could be regarded (at least in part) as a “decerebration syndrome which may result from birth trauma.”
- Somewhat surprisingly, nothing further was published on this topic until 1956 when Pasamanick and colleagues proposed their now-classic thesis of a “continuum of reproductive casualty,” whereby pregnancy and birth complications can lead to a gradient of injury extending from fetal and neonatal death through cerebral palsy, epilepsy, mental deficiency, and behavior disorder.
- The paper by Pasamanick and colleagues initially had its greatest impact on the field of child psychiatry.
- In the early 1960s, there were reports of significant associations between pregnancy complications (particularly toxemia, bleeding, and severe maternal illness) and childhood psychosis. However, diagnostic uncertainty about the classification of childhood psychosis seems to have halted research in this area. Even though a review in 1966 concluded that “the need for further researces is strongly indicated by these findings”
- There was a gap of 10 years before a study by Torrey and colleagues reported an association between bleeding in pregnancy and childhood psychosis.
Gene Expression in Schizophrenia - Genetics
Gene Expression in Schizophrenia - Genetics
Studies
Gene Expression Over the Course of Schizophrenia: From Clinical High-Risk For Psychosis to Chronic Stages
Gene Expression Over the Course of Schizophrenia: From Clinical High-Risk For Psychosis to Chronic Stages
Journal Published
npj Schizophrenia volume 5, Article number: 5
Year Published
2019
Authors / Collaborators
Vanessa Kiyomi Ota, Patricia Natalia Moretti, Marcos Leite Santoro, Fernanda Talarico, Leticia Maria Spindola, Gabriela Xavier, Carolina Muniz Carvalho, Diogo Ferri Marques, Giovany Oliveira Costa, Renata Pellegrino, Simone de Jong, Quirino Cordeiro, Hakon Hakonarson, Gerome Breen, Cristiano Noto, Rodrigo Affonseca Bressan, Ary Gadelha, Jair de Jesus Mari & Sintia I. Belangero
Full Article
GeneZExpressionZOverZTheZCourseZofZSchizophrenia.pdf
Hypothesis
To find genes related to a prepsychotic stage (i.e., genes differentially expressed in CHR compared to other groups), to an acute psychotic stage (i.e., genes differentially expressed in FEP compared to other groups), to a long-term psychotic state, or following a long exposure to antipsychotics (i.e., genes differentially expressed in CSZ compared to the other groups). The aim of the study is to determine whether patients with schizophrenia (SZ) at different clinical stages may help clarify what effects could be due to the disease itself, to the pharmacological treatment, or to the disease progression.
They further verified whether single-nucleotide polymorphisms (SNPs) could be related to gene expression differences.
Background
- Schizophrenia (SZ) is a heterogenous disorder, with a wide array of clinical, functional, and cognitive outcomes.
- The different disease trajectories, in which a patient can present distinct clinical and biological features of disease progression, are a one major source of heterogeneity.
- Clinical staging models have been proposed, but relatively few studies compare biological measures in the distinct stages.
- Although the heritability of schizophrenia is very high (~80%), genetics still lack a major impact in clinical practice.
- Gene expression, the transcription of a gene’s DNA information into an RNA copy, is also influenced by a combination of environmental and genetic factors, such as expression quantitative trait loci (eQTLs), which are genomic loci that contribute to variation in expression levels.
- Schizophrenia risk loci have been noted as being enriched for eQTLs.
- Although many studies have investigated gene expression in the blood of patients with schizophrenia, most were performed in patients with a long time of treatment and disease.
- Our previous studies have shown that antipsychotics affect gene expression and DNA methylation, suggesting that gene expression may be influenced by the time of treatment and disease.
- Other studies have investigated prodromal or FEP patients, but no study has compared RNA expression between patients in different stages.
Genetic Variants in Schizophrenia - Genetics
Genetic Variants in Schizophrenia - Genetics
Genetic variation is the differences in the DNA of a given species, a key to fitness and survival as it increases the chance of adaptability.
Genetics of Schizophrenia - Genetics
Genetics of Schizophrenia - Genetics
Studies
The Genetics of Schizophrenia
The Genetics of Schizophrenia
Journal Published
Research in Translation
Year Published
2017
Full Article
GeneticsZofZSchizophrenia.png
Hypothesis
The study will provide a high-level review of progress, its limitations, and the implications for clinical research and clinical practice.
Background
- There has been progress on research into the etiology of schizophrenia but particularly regarding the molecular genetics of this complex disorder of mind and brain.
- A number of critically important and unresolved issues remain that qualify the ultimate clinical and scientific validity of the results.
References
| Name of Article | Journal | Year | Authors | Website | Page |
| The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020 | Harvard University Press | 1996 | Murray CJL, Lozpe |
||
| The epidemiology of schizophrenia. | PLoS Med | 2005 | Saha S, Welham J, Chant D, McGrath J |
2: e141 | |
| A selective review of recent North American long-term followup studies of schizophrenia | Schizophr Bull | 1998 | McGlashan TH |
14: 515–542. | |
| Medical comorbidity in schizophrenia | Schizophr Bull | 1996 | Jeste DV, Gladsjo JA, Lindamer LA, Lacro JP |
22: 413–430. | |
| Excess mortality of mental disorder. | Br J Psychiatry | 1998 | Harris EC, Barraclough BB |
173: 11–53. | |
| The epidemiology of schizophrenia | Cambridge University Press. | 2003 | Murray RM, Jones PB, Susser E, van Os J, Cannon M |
470 p | |
| Effects of family history and place and season of birth on the risk of schizophrenia | N Engl J Med | 1999 | Mortensen PB, Pedersen CB, Westergaard T, Wohlfahrt J, Ewald H, et al. |
340: 603–608. | |
| Behavioral genetics in the postgenomic era, | 3rd ed. Washington, DC: APA Books | 2003 | Plomin R, DeFries JC, Craig IW, McGuffi n P |
414 p | |
| Schizophrenia as a complex trait: Evidence from a meta-analysis of twin studies. | Arch Gen Psychiatry | 2003 | Sullivan PF, Kendler KS, Neale MC |
60: 1187–1192 | |
| Genetics | American Psychiatric Publishing. In press | 2005 | Sullivan PF, Owen MJ, ODonovan MC, Freedman RR |
||
| From QTL to gene: The harvest begins | Nat Genet | 2002 | Korstanje R, Paigen B |
31: 235– 236 | |
| Genome scan metaanalysis of schizophrenia and bipolar disorder, part II: Schizophrenia | Am J Hum Genet | 2003 | Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, et al. |
73: 34–48. 13. Straub RE, | |
| A genomewide autosomal screen for schizophrenia susceptibility loci in 71 families with affected siblings: Support for loci on chromosome 10p and 6 | Mol Psychiatry | 2000 | Schwab SG, Hallmayer J, Albus M, Lerer B, Eckstein GN, et al. |
5: 638–649 | |
| An international two-stage genome-wide search for schizophrenia susceptibility genes. | Nat Genet | 1995 | Moises HW, Yang L, Kristbjarnarson H, Wiese C, Byerley W, et al. |
11: 321–324 | |
| A search for specifi c and common susceptibility loci for schizophrenia and bipolar disorder: A linkage study in 13 target chromosomes | Mol Psychiatry | 2001 | Maziade M, Roy MA, Rouillard E, Bissonnette L, Fournier JP, et al. |
6: 684–693 | |
| A schizophreniasusceptibility locus at 6q25, in one of the world’s largest reported pedigrees | Am J Hum Genet | 2001 | Lindholm E, Ekholm B, Shaw S, Jalonen P, Johansson G, et al. |
69: 96–105 | |
| Additional support for schizophrenia linkage on chromosomes 6 and 8: A multicenter study. Schizophrenia Linkage Collaborative Group for Chromosomes 3, 6 and 8 | Am J Med Genet | 1996 | Schizophrenia Linkage Collaborative Group. |
67: 580–594. | |
| Genetic case-control association studies in neuropsychiatry | Arch Gen Psychiatry | 2001 | Sullivan PF, Eaves LJ, Kendler KS, Neale MC |
58: 1015–1024. | |
| Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: A large-scale association study plus meta-analysis | Biol Psychiatry | 2005 | Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, et al. |
57: 139–144 | |
| A highly significant association between a COMT haplotype and schizophrenia. | Am J Hum Genet | 2002 | Shifman S, Bronstein M, Sternfeld M, PisanteShalom A, Lev-Lehman E, et al |
71: 1296–1302 | |
| The inherited basis of diabetes mellitus: Implications for the genetic analysis of complex traits. | Annu Rev Genomics Hum Gene | 2003 | Florez JC, Hirschhorn J, Altshuler D |
4: 257–291 | |
| Complement factor H polymorphism in age-related macular degeneration | Science | 2005 | Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. |
308: 385–389. | |
| Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration | Am J Hum Genet | 2005 | Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, et al. ( |
77: 149–153. | |
| From the cover: A common haplotype in the complement regulatory gene factor H (HF1/ CFH) predisposes individuals to age-related macular degeneration | Proc Natl Acad Sci U S A | 2005 | Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, et al. |
102: 7227–7232 | |
| Complement factor H polymorphism and age-related macular degeneration | Science | 2005 | Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, et al. |
308: 421–424 | |
| Complement factor H variant increases the risk of age-related macular degeneration. | Science | 2005 | Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, et al. |
308: 419–421 | |
| Effect of therapeutic innovation on perception of disease and the doctor-patient relationship: A history of general paralysis of the insane and malaria fever therapy, 1910–1950 | Am J Psychiatry | 1995 | Braslow JT |
152: 660–665. |
The Role of Genetics in the Etiology of Schizophrenia
The Role of Genetics in the Etiology of Schizophrenia
Full Article
TheZRoleZofZGeneticsZinZtheZEtiologyZofZSchizophrenia.pdf
Hypothesis
The aim of the study is to introduce the reader to the genetics of schizophrenia - its background, the status of a variety of genetic findings, new developments and current and future
Background
- Genome-wide experiments have discovered uncommon copy number variations (mainly deletions) associated with schizophrenia as well as common SNPs with alleles associated with schizophrenia.
- The aggregate data provide initial support for polygenic inheritance and for genetic overlap of schizophrenia with autism and with bipolar disorder.
- It is anticipated that the application of a myriad of tools from systems biology will lead to a delineation of biological pathways involved in the pathophysiology of schizophrenia and eventually to new therapies as genetic discoveries accumulate challenges.
Recent Advances in the Genetics of Schizophrenia
Recent Advances in the Genetics of Schizophrenia
University or Organisation
Johns Hopkins University
School, Department or Faculty
Institute of Genetic Medicine & Department of Psychiatry
Journal Published
Molecular Neuropsychiatry
Year Published
2018
Authors / Collaborators
Dimitrios Avramopoulos
Full Article
RecentZAdvancesZinZtheZGeneticsZofZSchizophreniaZPDF.pdf
Hypothesis
- Focus on genetic variation showing robust associations with schizophrenia including high-penetrance rare variants and low penetrance common variants
- Describe transcriptomics work
- Provide an alternative approach to the genetics of the disease
- The use of alternative phenotypes termed endophenotypes, which is widening our understanding of the dimensionality of mental illness.
- Discuss how cutting-edge technologies are opening new directions in the ways we can experimentally model Schizophrenia
Background
- The last decade brought tremendous progress in the field of schizophrenia genetics.
- As a result of extensive collaborations and multiple technological advances, we now recognize many types of genetic variants that increase the risk. These include:
- Large copy number variants
- Rare coding inherited
- De novο variants
- Over 100 loci harboring common risk variants.
- While the type and contribution to the risk vary among genetic variants, there is concordance in the functions of genes they implicate, such as those whose RNA binds the fragile X-related protein FMRP and members of the activity-regulated cytoskeletal complex involved in learning and memory.
- Gene expression studies add important information on the biology of the disease and recapitulate the same functional gene groups.
- Studies of alternative phenotypes help us widen our understanding of the genetic architecture of mental function and dysfunction, how diseases overlap not only with each other but also with non-disease phenotypes.
- The challenge is to apply this new knowledge to prevention and treatment and help patients.
- The data generated so far and emerging technologies, including new methods in cell engineering, offer significant promise that in the next decade we will unlock the translational potential of these significant discoveries.
Aging & Schizophrenia - Lifespan
Aging & Schizophrenia - Lifespan
Studies
Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions
Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions
Journal Published
Schizophrenia Bulletin, Volume 44, Issue 2, March 2018, Pages 398–408,
Year Published
2017
Full Article
SystemicZBiomarkersZofZAcceleratedZAgingZinZSchizophrenia.pdf
Hypothesis
This study aims to evaluate evidence for accelerated biological aging in schizophrenia using systemic markers of biological aging.
-
Are aging-related biomarkers abnormal in schizophrenia?
-
Which biomarkers are specifically involved in aging in schizophrenia?
-
What clinical characteristics in schizophrenia are risk vs protective factors for accelerated biological aging?
-
Are aging-related biomarkers abnormal in schizophrenia?
-
Which biomarkers are specifically involved in aging in schizophrenia?
Background
-
Schizophrenia is associated with markedly increased physical comorbidity and mortality.
-
Physiological changes seen throughout the body with normal aging occur at an earlier age in people with schizophrenia than in healthy comparison subjects (HCs).
-
Younger adults with schizophrenia are prone to diseases associated with aging such as diabetes and cardiovascular disorders
-
The average life span of a person with schizophrenia is 15–20 years shorter than that of an unaffected person
-
Patients with schizophrenia have 2–12 times higher mortality rate than age-comparable general population.
-
Given that lifespans are generally increasing for the population as a whole, understanding alterations in the aging process within schizophrenia is clearly imperative
-
Two-thirds of the excess deaths in schizophrenia are not from suicide, but due to “natural causes” such as cardiac and metabolic disorders.
-
This has led to a provocative suggestion that schizophrenia is not only a brain disease but rather, a disease of the whole body.
-
Prior attempts to address systemic biological defects in schizophrenia failed,at least in part, because of a lack of specific and sensitive systemic biomarkers of aging.
-
Several prior reviews have examined accelerated aging in schizophrenia from various perspectives (including metabolic disease cognition, brain structure, telomere length (TL),and oxidative stress, however, no publication, to our knowledge, has provided a comprehensive review of multiple biomarkers relevant to the hypothesis of accelerated biological aging in schizophrenia.
-
Although many comparisons and similarities have been drawn between schizophrenia and normal aging, we have a limited understanding as to which biomarkers are most altered with age in schizophrenia.
-
The identification of biological factors that underlie alterations in the aging process may permit identification of individuals at high risk for accelerated aging, and potentially open up consideration of new avenues for intervention.
-
Though the recent literature has frequently used the term “accelerated biological aging,” no review has synthesized evidence for this claim at system level.
Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study
Accelerated Brain Aging in Schizophrenia: A Longitudinal Pattern Recognition Study
Journal Published
Am J Psychiatry
Year Published
2016
Full Article
AcceleratedZBrainZAgingZinZSchizophrenia.pdf
Hypothesis
Does the progressive brain loss in schizophrenia reflect accelerated aging of the brain, or is it caused by a fundamentally different process?
Background
- Cross-sectional MRI studies have convincingly shown that brain volumesin schizophrenia patients are smaller than those in healthy subjects.
- Some of these abnormalities (such as changes in white matter volume and structure) are present beforeillness onset and aremostlikely of a developmental, possibly genetic, nature and appear to be stable over time.
- In contrast, other brain changes (such as reductionsin gray matter volume) become more pronounced during the course of the illness.
- Although several studies suggest that gray matter volume reductions are related to outcome, psychosis, relapses, medication, cannabis use, and genetic liability, the cause and nature of the progressive loss of gray matter are still unclear.
- Indeed, despite the multitude of longitudinal neuroimaging studies, a basic question on the progressive brain loss in schizophrenia remains unaddressed.
Neurobiology & Schizophrenia - Neuroscience
Neurobiology & Schizophrenia - Neuroscience
Neurobiology is the study of cells of the nervous system and the organization of these cells into functional circuits that process information and mediate behavior. As a subdiscipline of both biology and neuroscience, neurobiology has a significant impact of the development of schizophrenia.
Studies
Neurobiology of Schizophrenia
Neurobiology of Schizophrenia
Journal Published
Neuron Volume 52, Issue 1, 5 October
Year Published
2006
Abstract
NeurobiologyZofZSchizophrenia.html.txt
Hypothesis
- The review provides a definitive study of the neurobiology of schizophrenia is now possible.
- The neurobiological study of schizophrenia may help illuminate the nature of normal thought, perception, and emotion.
- Understanding schizophrenia may help us better understand human nature itself.
Background
- Schizophrenia affects about 0.5 to 1.0 percent of the population worldwide with devastating consequences for affected individuals and their families, is the seventh most costly medical illness to our society
- The available symptomatic treatment is only partially successful, and therefore the development of rational therapeutics, based on an understanding of the etiology and pathogenesis of schizophrenia, is imperative.
- Until recently, progress in schizophrenia has been painfully slow and limited by a number of factors, including the heterogeneity of the schizophrenia phenotype and the lack of clear pathological lesions like those that have provided reference points in the study of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurodegenerative disorders.
- Investigation into the mechanism of action of the drugs used to treat schizophrenia has not provided clear understanding of the pathogenesis of the disease.
- While schizophrenia is highly heritable (it has a heritability score of approximately 0.8), the genetics are complex and the interpretation of genetic data has proven difficult.
- Now, however, advances in phenotypic analysis, neuroimaging, genetics, and molecular pathology provide the basis for optimism. Schizophrenia can be understood, at least in part, as a subtle disorder of brain development
- Evidence now supports an etiologic role for mutations or polymorphisms in a number of genes as well as obstetrical and premorbid abnormalities of development and cognition.
Neurobiology of Schizophrenia Onset
Neurobiology of Schizophrenia Onset
School, Department or Faculty
Laboratory of Cellular Neuropathology (McLean Hospital); Department of Psychiatry (Beth Israel Deaconess Medical Center); Department of Psychiatry (Harvard Medical School).
Journal Published
Current Top Behaviour Neuroscience
Year Published
Tsung-Ung W. Woo
Abstract
NeurobiologyZofZSchizophreniaZOnset.pdf
Hypothesis
This review discusses the possible pathophysiological mechanisms that may contribute to the dysfunction of PV neurons in schizophrenia, focusing on:
- Deficient glutamatergic innervation
- Oxidative stress and
- Impaired formation of ECM structures called perineuronal nets (PNNs).
Background
-
Schizophrenia is a complex, prevalent, and extremely debilitating brain disorder affecting approximately 1% of the population worldwide.
-
It is defined by a constellation of positive (i.e., delusions and hallucinations) and negative (i.e., affective flattening, avolition, alogia, anergia, and anhedonia) symptoms.
-
In addition, patients exhibit prominent cognitive deficits (such as disturbances in executive functions), working memory, and attention.
-
Together, these symptoms and cognitive deficits render the individuals inflicted with the illness a life-long course of intellectual, vocational, interpersonal and social impairment.
-
At present, antipsychotic medications provide some symptomatic relief in some but not all patients, but they do not appear to impact the course or the long-term outcome of the illness in any meaningful fashion.
-
The current lack of truly effective treatment, in no small part, is because after decades of research the pathophysiological basis of schizophrenia remains poorly understood.
-
It has long been known that the onset of schizophrenia typically occurs during the period of late adolescence and early adulthood. In recent years, there has been growing emphasis in the field in identifying the clinical characteristics that immediately precede the onset of full-blown illness
-
The clinical symptoms and cognitive and functional deficits of schizophrenia typically begin to gradually emerge during late adolescence and early adulthood.
-
The underlying concept is that timely intervention during this critical phase of the pathogenetic process could attenuate or perhaps even prevent the onset of overt symptoms and deficits.
-
Although this line of research has evoked significant optimism and enormous excitement, reliable methods to faithfully predict who will ultimately develop symptoms and deficits do not yet exist.
-
Perhaps more importantly, it is far from clear as to what preventative or early intervention strategies would be effective.
-
The single most significant impediment is that the neurobiological mechanisms that mediate the onset of illness are at present virtually unknown.
-
The period of adolescence is a time of profound changes, when the highest-order cognitive functions, such as reasoning, abstract thinking, and planning, gradually achieve maturation.
-
This maturational process is thought to reflect the coming online of the executive brain system of the cerebral cortex, orchestrated in large part by the maturation of the prefrontal cortex (PFC) via extensive pruning of excitatory synapses, dendritic spines on pyramidal neurons on which these synapses form, and axon terminals of pyramidal neurons that are presynaptic to these synapses.
-
This connectional pruning process is associated with the maturation of the capacity of PFC pyramidal neuronal networks to oscillate and synchronize, especially in the gamma (i.e., 30–80 Hz) frequency band
-
In addition, gamma band oscillation appears to be an electrophysiological correlate of working memory, a core PFC function that is required for the integrity of executive functioning.
-
Interestingly, in patients with schizophrenia, working memory and executive functioning are compromised and gamma band oscillation has repeatedly been shown to be impaired.
-
The fact that many of the symptoms and cognitive deficits of schizophrenia typically begin to emerge during late adolescence and early adulthood has long led to the hypothesis that disturbances of the synaptic pruning process that occurs in the PFC during this period may play a role in triggering the onset of illness, although the specific neurobiological mechanisms that underlie the presumed synaptic pruning disturbances have not been systematically formulated. T
-
his is in large part due to the fact that, for a long time, the biological determinants of this synaptic pruning process were completely unknown. However, recent studies in rodents have identified the maturation of intracortical inhibition subserved by the parvalbumin (PV)-containing inhibitory neurons and the formation of extracellular matrix (ECM) environment as two important mechanisms that regulate the time course of the critical period for developmental synaptic plasticity in the cerebral cortex
-
Interpretation of these findings in the context of our current understanding of neuronal type-specific regulation of gamma band oscillation and PFC circuit dysfunction in schizophrenia allows us to begin to develop specific, experimentally testable hypotheses of the neurobiology of developmental synaptic pruning in the human PFC and the possible pathophysiological mechanisms of schizophrenia onset.
-
Specifically, it is postulated that the inhibitory neurons that contain PV may play a central role in regulating the time course of PFC synaptic pruning during late adolescence and arly adulthood and that disturbances of PV neurons may lead to aberrant loss of synapses and thereby cortical circuitry instability, hence triggering the onset of schizophrenia
Neurobiology of schizophrenia: search for the elusive correlation with symptoms
Neurobiology of schizophrenia: search for the elusive correlation with symptoms
School, Department or Faculty
Psychiatry Service (San Francisco VA Medical Center); Department of Psychiatry (University of California)
Journal Published
Frontiers in Human Neuroscience
Year Published
2012
Authors / Collaborators
Daniel H. Mathalon and Judith M. Ford
Abstract
NeurobiologyZofZSchizophreniaZZSearchZforZtheZElusiveZCorrelationZWithZSymptoms.pdf
Full Article
NeurobiologyZofZSchizophrenia_1.html.txt
Hypothesis
This paper provides an overview of the myriad conceptual and methodological obstacles that undermine efforts to link the severity of specific symptoms to specific neurobiological measures, obstacles that ultimately impede progress toward elucidating the neurobiological mechanisms underlying these symptoms.
Background
- Advances in neuroscience methods over the past 50 years have provided the means to study complex psychiatric disorders in vivo, firmly establishing that disorders once viewed as psychological reactions to stressful environments (particularly family environments) are associated with subtle abnormalities in brain structure and function.
- This historical transition toward reconceptualizing psychiatric disorders as brain disorders is exemplified by the paradigm shift that gave primacy to neurobiological and neurodevelopmental perspectives in understanding the etiopathology of schizophrenia.
- Despite the clinical heterogeneity of schizophrenia, a wide variety of neurobiological abnormalities have been replicated across clinical samples and research laboratories, providing some support for the neurobiological validity of the clinical criteria used to diagnose patients.
- Efforts to understand the neurobiological bases of the clinical heterogeneity that schizophrenia comprises, mainly by correlating neurobiological measures with specific symptoms, have been largely unsuccessful.
- Inconsistency” has been the most consistent finding to emerge from such efforts.
Neuroethics in Schizophrenia - Neuroscience
Neuroethics in Schizophrenia - Neuroscience
Neuroethics is an interdisciplinary research area that focuses on ethical issues raised by our increased and constantly improving understanding of the brain and our ability to monitor and influence it, as well as on ethical issues that emerge from our concomitant deepening understanding of the biological bases.
Neuropsychology Profile of Schizophrenia - Neuroscience
Neuropsychology Profile of Schizophrenia - Neuroscience
The neuropsychological profile is typically characterized by prominent specific deficits in memory and learning, working memory, executive functions, attention, and processing speed, which are evident on a background of a generalized cognitive deficit.
Dopamine Dysfunction in Schizophrenia - Pathophysiology
Dopamine Dysfunction in Schizophrenia - Pathophysiology
The dopamine hypothesis of schizophrenia came from ::
- Post-mortem studies finding increased striatal availability of D2/D3 receptors in the striatum
- Studies finding elevated CSF levels of dopamine metabolites
- Most antipsychotics having affinity for D2 receptors.
- A link between striatal dopamine synthesis and positive symptom
- A link betweenincreased and decreased dopamine transmission in subcortical and cortical regions.
- Findings in presynaptic dopamine function
- Disruption of the auditory thalamocortical projections give rise to hallucinations
- Dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions.
- Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex
- Unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D1 and NMDA receptor stimulation
- Hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.
Glutamate Abnormalities - Pathophysiology
Glutamate Abnormalities - Pathophysiology
Schizophrenia research has focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition. Glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function. Glutamate can affect dopamine function suggesting an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Mutations in genes related to glutamatergic neurotransmission includ GRIN2A, GRIA1, SRR and GRM3.
Interneuron Dysfunction in Schizophrenia - Pathophysiology
Interneuron Dysfunction in Schizophrenia - Pathophysiology
Dysfunction of interneurons in the brain is closely relates to the glutamate hypothesis, as interneurons in the brain are GABAergic and local, and function mainly through the inhibition of other cells. One type of interneuron, the fast-spiking, parvalbumin-positive interneuron, has been suggested to play a key role in schizophrenia pathophysiology. EEG studies have indirectly also pointed to interneuron dysfunction in schizophrenia, pointing to abnormalities in oscillatory activity in schizophrenia, particularly in the gamma band (30–80 Hz). Gamma band activity appears to originate from intact functioning parvalbumin-positive interneuron.[29] Together with the post-mortem findings, these EEG abnormalities point to a role for dysfunctional parvalbumin interneurons in schizophrenia.
Myelination & Schizopghrenia - Pathophysiology
Myelination & Schizopghrenia - Pathophysiology
Myelination abnormality are a core pathophysiology of schizophrenia. From structural imaging studies that white matter regions in addition to grey matter regions, showed volumetric reductions in patients with schizophrenia . In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in post-mortem brains of schizophrenia patients. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies. It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells as these have been found to be intact in schizophrenia brains.
Tardive Dyskinesia & Antipsychotics - Pharmaceuticals
Tardive Dyskinesia & Antipsychotics - Pharmaceuticals
Tardive dyskinesia is a severe complication of long-term use of antipsychotics, characterized by a wide range of abnormal involuntary movements involving mouth, tongue, jaw or any other part of the body. Dyskinesia can be seriously disabling in its more severe forms and may affect walking, eating and breathing.
Birthing Complications & Schizophrenia - Trauma
Birthing Complications & Schizophrenia - Trauma
-
Obstetric complications or events
-
Maternal Stress
-
Fetal Growth
-
Low birthweight
-
Cerebral atrophy
-
Foetal Hypoxia at or immediately after birth
-
Prenatal stress
-
Intrauterine malnutrition
-
Prenatal infection
-
Paternal age
-
Chromosomal aberrations and mutations
-
Adverse prenatal environment.
-
A complex interaction between maternal genotype, maternal behavior, prenatal environment and possibly medication
-
Caeliac Disease (Gluten Intolerance)
-
Exposure to toxins such as lead
-
High neuroticism increases
Postpartum Psychosis - Trauma
Postpartum Psychosis - Trauma
Studies
Obstetric Variables Associated With Bipolar Affective Puerperal Psychosis
Obstetric Variables Associated With Bipolar Affective Puerperal Psychosis
Journal Published
Br J Psychiatry
Year Published
2006
Authors / Collaborators
Emma Robertson Blackmore 1, Ian Jones, Monica Doshi, Sayeed Haque, Roger Holder, Ian Brockington, Nick Craddock
Full Article
obstetric-variables-associated-with-bipolar-affective-puerperal-psychosis.pdf
Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis
Risk of puerperal and non-puerperal recurrence of illness following bipolar affective puerperal (post-partum) psychosis
Journal Published
British Journal of Psychiatry
Year Published
2005
Authors / Collaborators
EMMA ROBERTSON, IAN JONES, SAYEED HAQUE, ROGER HOLDER EMMA ROBERTSON, IAN JONES, SAYEED HAQUE, ROGER HOLDER and NICK CRADDOCK