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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]

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

A. Introduction

• 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)

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.”

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

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

“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

“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

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

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.”

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)

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

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)

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

Prognosis

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%).

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

B. Causes of schizophrenia: neurobiology, environment, genetics

Neurotransmittersand schizophrenia

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

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)

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

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

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

Major dopaminergic systems in human brain

Prefrontal cortex,

nucleus accumbens, “limbic” areas

mPFC = medial prefrontal cortex

NAc = nucleus accumbens

BLA = amygdala, basolateral nucleus

VTA = ventral tegmental area

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

Hypodopaminergic activity in the prefrontal cortex (PFC) may cause

hyperdopaminergic activity in limbic areas

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

Glutamate: AMPA and NMDA subtypes ofionotropic glutamate receptors

PCP = phencyclidine

Ketamine-induced thought disorders closely resemble those in schizophrenia patients

(Alder CM et al, Am J Psychiatry 156, 1646-1649, 1999)

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

Allosteric activators of the NMDA receptor that bind to the glycine binding site may ameliorate

negative symptoms and improve cognition

D-cycloserine

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

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.

*

Neurodevelopment

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

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)

Excessive synaptic pruning/neurodegeneration

Dramatic loss of brain grey matter is observed in very early-onset schizophrenia

Thompson PM et al., PNAS 98, 2001

Grey matter losses increase during the course of the illness

Thompson PM et al., PNAS 98, 2001

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

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”

Second-generation antipsychotics may provide protection from excessive grey matter loss

Thompson PM et al., Cerebral Cortex, 2009

Environmental risk factors

Early insults increase the risk of developing schizophrenia

(Sullivan PF, PLoS Medicine 2, e212, 2005)

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

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

Genetics

Schizophrenia: family ties

Gottesman II and Erlenmeyer-Kimling L, Schizophrenia Research 51, 2001

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

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

Genetic linkage studies have identified a large number of schizophrenia-risk loci

(Sullivan PF, PLoS Medicine 2,2005)

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

Copy number variants (CNVs) associated with schizophrenia

Gulsuner S and McClellan JM, Neuropsychopharmacology Reviews, 2015

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

De novo mutations in schizophrenia map to genes activeduring the fetal development of the prefrontal cortex

Gulsur S et al, Cell, 2013

Schizophrenia susceptibility loci

Kotlar AV et al, Eur J Med Gen, 2015

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

The genetic “architecture” of schizophrenia

Sullivan PF, Daly MJ and O‟Donovan M, Nature Reviews Genetics, 2012

Toward the development of novel therapeutic approaches for treating

and preventing of schizophrenia

Schizophrenia: a working model

Genetic predisposition

Neurodevelopmentalabnormalities (early)

Neurodevelopmentalabnormalities (late)

Neurodegeneration

Environmental insults

Stress

Psychosis

Prodromal stages

Schizophrenia

Premorbid stage

Interaction of genetic and environmental risk factorsin the developmental pathology of schizophrenia

Owen MJ, Sawa A, Mortensen PB, Lancet, 2016

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

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

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!

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

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

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

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

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

Additional Slides

• 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

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

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

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)

A “Developmental” model for schizophrenia

Murray RM et al, European Neuropsychopharmacology 18, 2008

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

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

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.

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

DISC1

Wu, Q, Li Y& Xiao B,Gene 2013

Trans-

location

Mental

Illness

+ +

+ -

- +

- -

DISC1 binding proteins and DISC11 rare mutations linked to mental disorders

Brandon NJ and Sawa A, 2011

Cell autonomous

DISC1-related

functions

Narayan, Nakajima, & Sawa,The Neuroscientist, 2013

neuronal migration

neurite outgrowthneural progenitor

cell proliferation

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

*

* * *

*

Hypothesized DISC1 x “environmental” interactions

Narayan, Nakajima, & Sawa,The Neuroscientist, 2013 CMV = cytomegalovirus

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

Copy number variants (CNVs) associated with schizophrenia (Sullivan et al, 2012)

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

Updated view of the genetic “architecture” of schizophrenia

Owen MJ, Sawa A, Mortensen PB, Lancet, 2016 (Appendix)

(CIs = confidence intervals)