lecture 2 schizophrenia - fudan universitymedicine.fudan.edu.cn/.../files/schizophrenia.pdf ·...
TRANSCRIPT
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Lecture 2Schizophrenia
David Saffen, Ph.D.Professor/Principal Investigator
Department of Cellular and Genetic MedicineFudan University, Shanghai, China
Email: [email protected]
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OutlineA. Introduction
- A brief history of schizophrenia (SCZ)- Core clinical features - Diagnosis, clinical course and management- Epidemiology and societal burden - Famous individuals with schizophrenia
B. Causes of schizophrenia: neurobiology, environment, genetics- Neurotransmitters and SCZ - Neurodevelopment- Excessive synaptic pruning/neurodegeneration- Environmental risk factors - Genetics
C. Toward the development of novel therapeutic approaches for treating and preventing of schizophrenia
D. References, schizophrenia resources, additional slides
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A. Introduction
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• Early descriptions
- No clear description of a disease meeting the currently
accepted symptoms of schizophrenia prior to 1809
(James Tilly Mathews/Philppe Pinel) although ancient
sources described psychological states corresponding to
psychosis, mania, and depression (melancholia).
- First systematically classified as a distinct disorder by
Emil Kraepelin (1893) and Eugen Bleuler (1908)
A brief history of schizophrenia (SCZ)
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Eugen Bleuler (1857-1939)
Swiss psychiatristUniversity of Zurich
Coined the word “schizophrenia” (1908).
Identified disturbances in 1) association and 2) affect, and 3) “ambivalence*,” and
4) autism as the core symptoms.
Emil Kraepelin(1956-1926)
German psychiatristUniversities of
Heidelberg and MunichIdentified “dementia praecox”
and manic-depression asdistinct disorders (1893)
Note: “schizo”-”phrenia” from the Greek for “split” and “mind” was coined to emphasize the dissociation of
personality, thinking, memory and perception. It does not refer to the presence of multiple personalities
within a single individual, a rare condition currently diagnosed as “Dissociative Identity Disorder.”
*”ambivalence”: the simultaneous holding of contradictory emotions or thought: “Once I felt joy, but it was not pleasant.”
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Early therapies
• Isolation/restraint/sedatives (from early-mid 1800s)• Psychoanalysis (early 1900s)• Insulin shock (1930s)• Electroconvulsive shock therapy (ECT; 1940s)• Frontal lobotomy*
(1936 – late 1960s; > 20,000 performed in the United States!)
None of these treatments is specific or very effective; Several are clearly harmful.
*Aka frontal “leucotomy”: developed by Antonio Egus Moniz, Portuguese neurologist, recipient of 1949 Nobel Prize in Physiology or Medicine; popularized and dramatically abused by American physician Walter Freeman, who developed the “ice-pick” transorbital lobotomy
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Modern drug therapy
- Chlorpromazine (1952) Heri Laborit, Paris surgeon: tested antihistamines as anesthesia supplements; Pierre Deniker, French psychiatrist, tested drug in psychiatric patients)
- “First Generation” antipsychotics:
thorazine (chlorpromazine), haloperidol (butyrophenone)
- “Second” generation” antipsychotics:
pimozide, molindone, loxapine, clozpine, olanzapine,
quitiapine, risperidone, ziprasidone, aripiprazol
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“Positive” symptoms:- delusions
persecutory, referential, somatic, religious, grandiose, bizarre
- hallucinationsaural, visual, tactile, olfactory, gustatory
- disorganized speechderailment, loose associations, tangentiality, incoherence
- disorganized or “catatonic” behaviorpoor hygiene, inability to carryout daily tasks, inappropriatedress, inappropriate sexual behavior, unpredictable agitation;stupor, rigidity, posturing, excitement
Core clinical features
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“Negative” (deficit) symptoms:
- affective flatteningimpoverished facial expressions and body language, poor eye contact
- alogiapoverty of speech
- avolitioninability to initiate and continue goal-directed behaviors
also often observed:- anhedonia
inability to experience pleasure, joy
Lack of awareness/insight concerning onesillness is a common feature of schizophrenia
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Diagnosis, clinical course and management
DSM-IV-TRTM
“Classical” subtypes: - Paranoid Type
- Disorganized Type- Catatonic Type- Undifferentiated Type - Residual Type
Alternative Dimensional Descriptors- Psychotic dimension: hallucinations/delusions
- Disorganized dimension: disorganized speech orbehavior; inappropriate affect
- Negative (deficit) dimension: affective flattening,alogia, avolition
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DSM-5 Diagnostic criteria
A. Two or more characteristic symptoms, each present for a significant portion of time during one month (or less if successfully treated):
1) delusions 2) hallucinations 3) disorganized speech 4) grossly disorganized
or catatonic behavior 5) negative symptoms
Presence of bizarre delusions or internal voice maintaining running commentary on the individual‟s behavior or thoughts, alone sufficient to meet criteria “A.”
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B. Presence of social/occupational dysfunction: (affecting work, interpersonal relationships or self-care; for children or adolescents: failure to achieve expected levels of interpersonal, academic or occupational achievement.)
C. Duration: Continuous signs of disturbance for at least 6 months
Exclusions: 1) schizoaffective and mood disorders
2) substance/medical conditions3) autism or pervasive developmental disorder (PDD)
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Classification of longitudinal course, accessed after one year (DSM-5)
• Episodic with interepisode residual symptoms (with or without prominent negative symptoms)
• Episodic with no inter-episode residual symptoms
• Continuous (with or without prominent negative symptoms)
• Single episode in partial remission(with or without prominent negative symptoms)
• Single episode in full remission
• Other or unspecified
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Clinical course: Stages of illness in schizophrenia
Healthy
Gestation/ 10 Puberty 20 30 40 50Birth
WorseningSeverity ofSigns andSymptoms
Premorbid
ProdromalOnset/Progression
Deterioration
Chronic/Residual
Age (Y)
(After Lieberman JA, et al, J Clinical Psychiatry 67, 2006)
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Epidemiology and societal burden
• Narrowly defined: lifetime prevalence = 0.3 – 0.66%
Broadly defined: lifetime prevalence = 2.3% - 3.5%
• An estimated 24 million persons worldwide are affected (World Health Organization, 2011)
• Diagnosed 1.4 more frequently in males compared to females; Peak ages of onset are 20 - 28 for males and 26-32 for females
• Schizophrenia accounts for ~ 1% of all Disability-Adjusted Life Years (DALY),a measure of the burden of disease; one DALY = one yearof “healthy” life lost.
= 170 – 185 per 100,000= 275 – 290 per 100,000
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Prognosis
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Long-term issues• For a large percentage of individuals with schizophrenia, complete
remission is not obtained. Although antipsychotic medications are able to dampen the occurrence and intensity of hallucinations and delusions, negative symptoms and profound disturbances in cognition often are retained or worsen with time.
• The presence of these “residual” symptoms, often prevent affected individuals from returning to work or living independently.
• Many patients stop taking antipsychotic medications due to undesirable side effects, including obesity and the feeling of loss of “self.” Also, approximately 1/4 to 1/3 of schizophrenia patients are “treatment” resistant, failing to respond to even high dosages of antipsychotic drugs.
• The life-span of individuals with schizophrenia is reduced by 12 – 15 years compared to the unaffected population. Death is often related to reduced access to medical care and increased “life-style” risk factors, including poor diet, little exercise, obesity, smoking and alcohol consumption.
• Risk of suicide is also greatly enhanced. Suicide, often by violent means, is the major single cause of premature death among individuals with schizophrenia (estimated: 4-5%).
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Famous individuals with schizophrenia
John Nash
Mathematician (game theory)
Nobel Prize in Economics 1994
Eduard Einstein
Son of Albert Einstein
Tom Harrell
Jazz musician (trumpet)
composer; Tom Harrell quintet
Vaclay Nijinsky
Russian ballet dancer
Syd Barrett
Musician: singer,
electric guitar (Pink Floyd)
Elyn Saks
Professor of Law (USC)
MacArthur “Genius” Award
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B. Causes of schizophrenia: neurobiology, environment, genetics
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Neurotransmittersand schizophrenia
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Reserpine discovered to ameliorate psychosis
Reserpine (from Rauwolfia root):depletes monoamine neurotransmitters, including
dopamine, from nerve-endings. Has weak antipsychoticactivity, but serious side effects prevent
wide use as psychiatric drug. Circa: early 1950‟s
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Chlorpromazine (THORAZINE)the first effective antipsychotic drug
circa: 1950 (France)
Clozapine (CLOZARIL)A “second-generation”
antipsychotic drugCirca: 1990 (US)
Haloperidol (HALDOL)A “first generation”antipsychotic drug
circa: 1967 (US)
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All first- and second-generation antipsychotic drugs block D2
dopamine receptors
Dopamine
D2 receptors: members of the7-transmembrane class ofG protein-coupled receptors (GPCRs); activate Gi/o toinhibit adenylate cyclase
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Therapeutic potencies of antipsychotic drugs correlate with their affinity for dopamine D2 dopamine receptors
(P Seeman, Synapse 1, 133, 1987)
Range and average clinical dose for controlling schizophrenia (mg d-1)
D1 receptor binding D2 receptor binding
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D2 receptors are expressed at high levels in the striatum (caudate and
putamen) and nucleus accumbens
Statistical parametric map for [11]C-raclopride binding potential in human striatum(Transverse section) Pavese et al., Brain 126, 2007
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Major dopaminergic systems in human brain
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Prefrontal cortex,
nucleus accumbens, “limbic” areas
mPFC = medial prefrontal cortex
NAc = nucleus accumbens
BLA = amygdala, basolateral nucleus
VTA = ventral tegmental area
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Dopaminergic hypothesis for schizophrenia:
• Hyperdopaminergic activity in “limbic” areas (especially the ventral striatum and nucleus accumbens) contribute to positive symptoms, especially psychosis and delusions
• Hypodopaminergic activity in the prefrontal cortex contribute to negative symptoms and cognitive impairments
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Hypodopaminergic activity in the prefrontal cortex (PFC) may cause
hyperdopaminergic activity in limbic areas
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Agents that increase levels of extracellular dopamine precipitate
psychosis in sensitive individuals
Amphetamine and methamphetamine:stimulate the release of dopamine from nerve terminals
L-DOPA, administered systemically for the treatment of Parkinson‟sdisease, is converted to dopamine in the brain
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Glutamate: AMPA and NMDA subtypes ofionotropic glutamate receptors
PCP = phencyclidine
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Ketamine-induced thought disorders closely resemble those in schizophrenia patients
(Alder CM et al, Am J Psychiatry 156, 1646-1649, 1999)
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Hypothesis: NMDA
hypofunction in
GABAergic
interneurons causes
excessive dopamine
release in the ventral
striatum and nucleus
accumbens
and decreased release
of dopamine in the
prefrontal cortex
Ellaithy A, et al,
Trends in
Neuroscience,
2015
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Allosteric activators of the NMDA receptor that bind to the glycine binding site may ameliorate
negative symptoms and improve cognition
D-cycloserine
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Metabotropic glutamate receptor agonists and positive
allosteric modulators (PAMs) are being explored as
possible therapeutic agents for treating schizophrenia
LY354740 A mGluR group II agonist
LY487379A mGluR2 PAM
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Anti-NMDA receptor encephalitis
Kayser MS and Dalmau J, Schizophrenia Research, 2016
*Most often associated with
ovarian teratomas,
but sometimes following
viral infections or immunizations.
*
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Neurodevelopment
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Evidence for neurodevelopmental disturbances in SCZ
Retrospective studies show that children who later develop schizophrenia have subtle motor, cognitive and social deficits, including:
poor motor development
poor language skills
low IQ
attention deficits
“executive function” deficits
“quasi-psychotic” mental events
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Many candidate schizophrenia genes identified in genetic studies are related to neurodevelopment
Examples include:
• Disrupted in Schizophrenia (DISC1)
• Neuregulin (NGR1)
• Neurexin1 (NRXN1)
• Contactin-associated protein-2 (CNTNAP2)
• Dysbindin (DTNBP1)
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Excessive synaptic pruning/neurodegeneration
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Dramatic loss of brain grey matter is observed in very early-onset schizophrenia
Thompson PM et al., PNAS 98, 2001
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Grey matter losses increase during the course of the illness
Thompson PM et al., PNAS 98, 2001
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Reductions in grey matter and brain volume arecorrelated with a reduction in synaptic connections,
rather than reductions in cell numbers
Glantz LA and Lewis DA, Arch Gen Psychiatry 58, 2001
Control
Schizophrenia 1
Schizophrenia 2
Golgi-stainedBasilar dendritesand spines of layer 3pyramidal cells in DLPFC
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Psychosis is accompanied by shrinkage of prefrontal cortex(T1-weighted MRI imaging study of ultra-high risk individuals)
Sun D et al., Schizophrenia Research 2008
“non-converter” “converter”
“difference”
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Second-generation antipsychotics may provide protection from excessive grey matter loss
Thompson PM et al., Cerebral Cortex, 2009
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Environmental risk factors
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Early insults increase the risk of developing schizophrenia
(Sullivan PF, PLoS Medicine 2, e212, 2005)
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Famine
• “Dutch Hunger Winter” 1944-1945
• Chinese famine during the “Great Leap Forward”
1959-1961
Song S, Wang W & Hu P, 2009
Infant mortalitySchizophrenia risk
urbanurban
urban
ruralrural
rural
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Additional risk factors:Exposure to stressors during adolescence and early adulthood may also contribute to pathological brain processes and precipitate the onset of psychosis
• Social adversity: being unemployed, being a immigrant (first and second generation), living in an urban environment, living alone, being single, having no close friends
• Life events: college, military service, failed loveaffair, marriage, divorce, loss of job, loss ofstatus, death in the family
• Illicit drug use in genetically susceptible individuals, especially: methamphetamine, cannabis
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Genetics
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Schizophrenia: family ties
Gottesman II and Erlenmeyer-Kimling L, Schizophrenia Research 51, 2001
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Estimations of SCZ heritability andconcordances in MZ and DZ twins
H2 for SCZ =0.80-0.85
Concordances:41-65% (MZ)0-28% (DZ)
Cardno AG & Gottesman II, Am J Med Gen, 2000
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Estimates of: 1) genetic contributions of common SNPs to liability for SCZ, BPD, MDD and ADHD and
2) shared genetic contributions to these psychiatric disorders
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Genetic linkage studies have identified a large number of schizophrenia-risk loci
(Sullivan PF, PLoS Medicine 2,2005)
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The most recent and largest (>34,000 cases) schizophrenia genome-wide association study (GWAS) identified
108 novel schizophrenia liability loci and confirmed an additional 20 loci.These relatively common genetic variants are linked to genes that
function in dopamine or glutamate neurotransmission, synaptic functions, and (surprisingly!) immune system functions.
PGC schizophrenia working group, Nature 511, 421-424, 2014
MHC
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Copy number variants (CNVs) associated with schizophrenia
Gulsuner S and McClellan JM, Neuropsychopharmacology Reviews, 2015
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Whole exome sequencing (WES) and whole genome sequencing (WGS)have implicated rare de novo mutations in synaptic networks as
candidate schizophrenia liability genes; some mutations are also linked to ASD and intellectual disability (ID)
Fromer M et al, Nature , 2014
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De novo mutations in schizophrenia map to genes activeduring the fetal development of the prefrontal cortex
Gulsur S et al, Cell, 2013
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Schizophrenia susceptibility loci
Kotlar AV et al, Eur J Med Gen, 2015
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Convergence of candidate liability genes
• Genes related to synaptic plasticity
ARC signaling complex, NMDAR complex,
Voltage-gated ion channels, FMRP pathway
• Genes related to glutamate/GABA signaling
GRM3, RGS4, DAOA, DAAO, PRODH2, GAD1
• Genes related to dopamine signaling
DRD2, (DRD1), COMT
• Genes related to neurodevelopment
DISC1, NRG1, ERBB4, DNTBP1, NRXN1, CNTNAP2
• Genes related to the immune system
MHC locus, C4, CSMD1
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The genetic “architecture” of schizophrenia
Sullivan PF, Daly MJ and O‟Donovan M, Nature Reviews Genetics, 2012
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Toward the development of novel therapeutic approaches for treating
and preventing of schizophrenia
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Schizophrenia: a working model
Genetic predisposition
Neurodevelopmentalabnormalities (early)
Neurodevelopmentalabnormalities (late)
Neurodegeneration
Environmental insults
Stress
Psychosis
Prodromal stages
Schizophrenia
Premorbid stage
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Interaction of genetic and environmental risk factorsin the developmental pathology of schizophrenia
Owen MJ, Sawa A, Mortensen PB, Lancet, 2016
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Early detection of individuals at risk
• Changes in scholastic performance
• Drug use, especially dopamine-related stimulants and cannabis
• “Quasi-psychotic” ideation
• Family history of mental illness
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Remarkable progress has been made during the last 60 years toward learning how to diagnose, treat, and possibly
prevent mental illnesses, however much work remains:
• Develop new therapeutic drugs that lack serious side-effects and are tailored to the individual
• Identify genes that contribute to mental illnesses as a step towards developing new drug targets and therapies
• Develop effective programs for the early detection and treatment of mental disorders to reduce symptoms and possibly prevent onset
• Develop better social support systems for persons with mental illnesses and for susceptible individuals
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Basic research will continue to provide the knowledge and insights needed to develop new ways of
diagnosing, treating and preventing the development of mental illness.
These advances must be accompanied by an increased awareness of the consequences of
neglecting to treat and care for the most vulnerable members of our society!
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References (1) • Owen MJ, Sawa A and Mortensen PB, Schizophrenia, Lancet 388, July 2, 2016
• Ripke S, et al, Biological Insights from 108 schizophrenia-associated genetic loci, Nature 511, 421-27, 2014
• Kotlar AV et al, New discoveries in schizophrenia genetics reveal neurobiological pathways: a review of recent findings, European Journal of Medical Genetics 58, 704-714, 2015
• Horvath S and Mirnics K, Schizophrenia as a disorder of molecular pathways, Biological Psychiatry, January, 2015
• Hall J, et al, Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity, Biological Psychiatry 77, 52-58, 2015
• Cross-disorder group of the Psychiatric Consortium, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis, Lancet 381, April 2013
• Adler CM et al, Comparison of Ketamine-induced thought disorder in healthy volunteers and thought disorder in schizophrenia, American Journal of Psychiatry 156, 1646-1649, 1999
• Allaithy A, et al, Positive allosteric modulators of metabotropic glutamate 2 receptors in schizophrenia treatment, Trends in Neuroscience 38, 2015
• Kayser MS and Dalmau J, Anti-NMDA receptor encephalitis, autoimmunity and psychosis, Schizophrenia Research 176, 36-40, 2016
• Muller N et al, The role of inflammation in schizophrenia, Frontiers in Neuroscience 9: 372, 2015
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References (2) • Cannon TD, How schizophrenia develops: cognitive and brain mechanisms underlying onset of
psychosis, Trends in Cognitive Sciences 19, December 2015.
• Rapoport JL Gledd & Gogtay, Neurodevelopmental model of schizophrenia: update 2012, Molecular Psychiatry 17, 1228-1238, 2012
• Gulsuner S et al, Special and temporal mapping of de novo mutation in schizophrenia to a fetal prefrontal cortical network, Cell 154, 518-529, 2013
• Toga A, Thompson PM and Sowell ER, Mapping brain maturation, Trends in Neuroscience 29, March 2006
• Thompson PM et al, Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-set schizophrenia, Proc. Natl. Acad. Sci. USA 98, 11650-55, 2001
• Sun D et al, Progressive brain structural changes mapped as psychosis develops in „at risk‟ individuals, Schizophrenia Research 108, 2009
• Thompson PM et al, Time-lapse mapping of cortical changes in schizophrenia with different treatments, Cerebral Cortex 19, 1107-1123, 2009
• Glantz LA and Lewis DA, Dendritic spine density in schizophrenia and depression, Arch. Gen. Psychiatry 58, 203, 2001
• Song S, Wang W, Hu P, Famine, death and madness: Schizophrenia in early adulthood after prenatal exposure to the Chinese Great Leap Forward Famine, Social Science & Medicine 68, 2009
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Additional reading
• Irving I Gottesman, Schizophrenia Genesis: The Origins of Madness, W.H. Freeman and Co. NY, 1991
• E Fuller Torrey, Surviving Schizophrenia, A Manual for Families, Consumers, and Providers, Fourth Edition, Quill (HarperCollins), NY, 2001
• Sylvia Nasar, A Beautiful Mind, Touchstone, NY, 1998
• Elyn Saks, The Center Cannot Hold: My Journey Through Madness, Hyperion Books, 2007
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Journal Presentation
• Background Article:
Broad Institute of MIT and Harvard press release: “Genetic
study provides first-ever insight into biological origin of
schizophrenia”
• Research Article:Sekar A, et al., Schizophrenia risk from complex variation of complement component 4, Nature, January 27, 2016
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Internet resources• National Institute of Mental Health (USA)
(http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml)
• Schizophrenia.com(http://www.schizophrenia.com/)
• National Alliance on Mental Illness (NAMI) (http://www.nami.org)
• Schizophrenia Research Forum(http://www.schizophreniaforum.org)
• Schizophrenia gene data base: SZGene: http://www.schizophreniaforum.org/res/sczgene/default.asp
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Additional Slides
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• ICD-10 (International Statistical Classification of Diseases and Related Health Problems, 10th Revision; World Health Organization)
(F20) :- Paranoid - Hebephrenic (= disorganized SCZ)- Catatonic- Undifferentiated- Post-schizophrenic depression- Residual schizophrenia- Other schizophrenia- Schizophrenia, unspecified
Disorder progression:- Continuous- Episodic with progressive deficit- Episodic with stable deficit- Incomplete remission- Complete remission- Other
Note: ICD-11 to be published in 2015
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Additional psychotic disorders (DSM-IVTR)
- Schizophreniform Disorder (with/without good prognostic indicators)
- Schizoaffective Disorder(Bipolar type, depressive type)
- Delusional Disorder(7 subtypes: erotomanic, grandiose, jealous, persecutory, somatic, mixed, unspecified)
- Brief Psychotic Disorder(with/without marked stressor(s), with postpartum onset)
- Shared Psychotic Disorder- Psychotic Disorder Due to a General Medical Condition
(with delusions, with hallucinations)- Substance-induced psychotic disorder
(with delusions, with hallucinations; with onset during intoxication,with onset during with withdrawal)
- Psychotic Disorder Not Otherwise Specified
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Schizophrenia spectrum and otherpsychotic disorders (DSM-5)
- Schizotypal (personality disorder) Disorder- Delusional Disorder
(7 subtypes: erotomanic, grandiose, jealous, persecutory, somatic, mixed, unspecified; specify if: with bizarre content)
- Brief Psychotic Disorder(specify: with/without marked stressor(s), with postpartum onset)
- Schizophreniform Disorder (specify: with/without good prognostic indicators)
- Schizophrenia- Schizoaffective Disorder (specify: bipolar type, depressive type)- Substance/Medication-Induced Psychotic Disorder
(with delusions, with hallucinations; with onset during intoxication,with onset during with withdrawal)
- Psychotic Disorder Due to Another Medical Condition(specify: with delusions, with hallucinations)
- Catatonic Disorder Due to Another Medical Condition- Unspecified Catatonia- Other Specified Schizophrenia Spectrum and other Psychotic Disorder- Unspecified Schizophrenia Spectrum and Other Psychotic Disorder
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Renaming of “schizophrenia” in Japan to reduce stigma of diagnosis (2002)
Seishin-bunretsu-byo 精神分裂病 (mind-split-disease)
Togo-shitcho-sho 統合失調症 (integration disorder)
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A “Developmental” model for schizophrenia
Murray RM et al, European Neuropsychopharmacology 18, 2008
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Model circuitry underlying NMDA hypofunction hypothesis for schizophrenia
inhibitorysubcortical projection neuron: e.g. in N. accumbens
excitatorythalamocortical neuron
excitatoryafferent neuron
(after Conn PJ et al, TRENDS in Pharmacological Sciences 30, 2009)
glutamate released inPFC
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NMDA-type glutamate receptor antagonists induce psychotic states and cognitive deficits
Ketamine“Special K”
Phencyclidine (PCP)“Angel dust”
PCP and ketamine induce psychosis, hallucinations and delusions at high brain concentrations
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DISC1 and mental illness
• Disrupted in schizophrenia (DISC1): located at the breakpoint of balanced translocation between chromosomes 1 and 11: t(1,11)(q42;q14).
• Highly associated with schizophrenia, bipolar disorder and major depression in large Scottish pedigree.
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Scottish pedigree that led to the discovery of DISC1
Brandon NJ and Sawa A, 2011;original report: St Clair D, et al, Lancet 336, 13-16
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DISC1
Wu, Q, Li Y& Xiao B,Gene 2013
Trans-
location
Mental
Illness
+ +
+ -
- +
- -
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DISC1 binding proteins and DISC11 rare mutations linked to mental disorders
Brandon NJ and Sawa A, 2011
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Cell autonomous
DISC1-related
functions
Narayan, Nakajima, & Sawa,The Neuroscientist, 2013
neuronal migration
neurite outgrowthneural progenitor
cell proliferation
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Cell non-autonomous
DISC1-related pathways
Narayan, Nakajima, & Sawa,The Neuroscientist, 2013
neuronal migration
neurite outgrowth
neural progenitor
cell proliferation
* = SCZ or BP disorder
candidate gene
*
* * *
*
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Hypothesized DISC1 x “environmental” interactions
Narayan, Nakajima, & Sawa,The Neuroscientist, 2013 CMV = cytomegalovirus
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DISC1 references
Narayan S, Nakajima K, & Sawa, A, DISC1: a key lead in studying cortical development and associated brain disorders, The Neuroscientist 19, 2013
Wu Q, Li Y & Xiao B, DISC1-related signaling pathways in adult
neurogenesis of the hippocampus, Gene 518, 223-230, 2013
Brandon NJ and Sawa A, Linking neurodevelopmental and synaptic theories of mental illness through DISC1, Nature Reviews Neuroscience 12, 202-722, 2011
Abazyan B, et al, Prenatal interaction of mutant DISC1 and immune activation produces adult psychopathology, Biological Psychiatry 68, 1172-81, 2010
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Copy number variants (CNVs) associated with schizophrenia (Sullivan et al, 2012)
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Whole genome and whole exome sequencing studies have identified rare (and possibly highly penetrant genetic variants and mutations)
that are enriched in genes encoding proteins that function in the synapse.
Hall et al, Biol. Psychiatry 2015
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Updated view of the genetic “architecture” of schizophrenia
Owen MJ, Sawa A, Mortensen PB, Lancet, 2016 (Appendix)
(CIs = confidence intervals)