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Schizophrenia

Dolores Malaspina, MD, MPH


Anita Steckler & Joseph Steckler Professor of
Psychiatry
Director of InSPIRES-
Institute for Social and Psychiatric Initiatives
Goal and Objectives
 Goal
• Introduce the concept of the etiology and
neurobiology of schizophrenia
 Objectives
• Describe genetic and environmental factors
involved in the risk of schizophrenia
• Describe brain findings in schizophrenia
• Describe course and comorbidity of
schizophrenia
Schizophrenia is:
Not:
“split personality”
ambivalence
“multiple personality”
Rather:
literally “split mind”
breaking of associations
“break with reality”
Schizophrenia
Complex Genetic Disorder
Early adulthood onset, deterioration
Psychosis, deficit in drive and emotions,
decline in function
Males often more ill and earlier onset
Common (0.5-1.5% of the population)
Comorbidity:
substance abuse, suicide
diabetes, cardiovascular disease,
less fertility, early mortality
Developmental origins
Degenerative disorder
Case Study
• John is a 20-year-old college student
• In sophomore year, began to withdraw from friends.
• Complained that classmates were breaking into room and
stealing his notes
• Though the college was listening to his phone calls and trying to
force him to leave school. He became preoccupied with the
hidden meanings of news reports that were directed to him.
• Grades began to deteriorate, did not complete writing
assignments, began to cut classes
• Started on antipsychotic medications and delusions resolved
• His grades continued to decline and he became more reclusive
Emil Kraepelin (1898)
Coined “Dementia Praecox”
 
Focussed on the illness
course.

“the disease attacks by


preference the frontal area of
the brain, the central
convolutions, and the
temporal lobe”
Our best clue as to the
etiology of schizophrenia was
the observation that it has a
strong hereditary
Schizophrenia is a psychosocial
disorder
a disturbed 1940’s
family– was
1970’sseen
as the as the major cause of
mental disorders
“Schizophrenogenic in the
mother”: a cold, US and
dominant
rejecting mother causes schizophrenia.
Family Disturbance: a mother who is aggressive,
domineering, or insecure; an inadequate, passive,
indifferent or threatening father
Double bind communication style – communications
with two conflicting messages.

The inability to define pathological brain


changes perpetuated the notion that it
was a functional disorder
Schizophrenia
Positive Symptoms
Additions or distortions to thought or behavior:
Hallucinations
sensory experiences without external stimulation
commonly auditory
Delusions
beliefs that are contrary to reality
commonly persecutory in nature
sometimes delusions of grandeur
Bizarre Behavior
Disorganized speech indicating a thought
disorder
Schizophrenia
Negative Symptoms
– Absence or insufficiency of normal behavior
– Distinguished from psychosis; “Positive Symptoms
Key Domains:
Deficits in emotional expression
Decrease in volition, social function
Spectrum of Negative Symptoms
– Flat affect – blunted facial expression
– Avolition (apathy/amotivation) – Inability to initiate
and persist in activities
– Asociality: severely impaired social relationships
– Anhedonia – Inability to experience pleasure
– Alogia – A relative absence of speech
Variability of Clinical Features in
SchizophreniaNegative
symptoms
Positive symptoms Avolition /
Delusions asociality
Hallucinations Emotional
Expression
deficits= flat
Functional Impairmentsaffect
Work/school
Anhedonia
Interpersonal relationships
Self-care Alogia
Motor Abnormalitie
Cognitive
deficits Catatonia
Attention
Memory Mood
Verbal fluency Disorganiza symptoms
Executive tion Depression/An
function Speech xiety
(eg, Aggression/Ho
abstraction) Behavior stility
Motor Suicidality
09_05
KH2F0905
Etiology: Strong familial
60
component
First-Degree Relative
50 48%
Second-Degree Relative 46%

40 Third-Degree Relative

Percentage Unrelated Person


of Risk 30

20 17%
13%
10 9%
5% 6% 6%
4%
1% 2% 2% 2%
0
Spouse Grand- Offspring of Offspring of
child Half One Two
First Schizophre- Schizophre-
Cousin Sibling nic Parent nic Parents
Uncle Parent
or Aunt
General Nephew Sibling
Population or Niece Fraternal Twin Identical
Twin
Family, Twin and Adoption Study Results
• Relatives of patients have a 5–10 fold increased risk versus
the general population which decreases by distance.

• Concordance rates for schizophrenia in monozygotic twins


are ~50%: this is 4 -fold higher than DZ twin pairs (10–15%),
which reflects the proportion of shared genes

• The adopted away child of an ill mother has the same risk as
if she raises the child herself, although the adoptive
environment may slightly alter risk.

Family, Twin and Adoption Studies Support Genes and Also


Provide Evidence For other factors of for the Environment
Brain imaging of discordant identical
twins
Candidate genes with strong
Gene
evidence Mechanism
DISC1 1q42.2 “Microtubule fx, cell migration, membrane
Disruption in Sz trafficking of receptors, Modulates neurite
outgrowth
DTNNBP1 6p22.3 Tethering postsynaptic receptors, synaptic
Dystrobrevin binding plasticity
protein 1
NRG1 8p12 CNS dev., Cell signalling Trans membrane
Neuroregulin proteins NMDA, GABA, & Ach receptors
(ligand for receptor tyrosine kinases of the
ErbB family)

RGS4 Regulator of G 1q23.2 Modulate signalling of G-protein linked receptors


protein signalling 4
COMT 22 Functional polymorphism (Val108/158Met)
Catechol O Methyl that moderates dopamine availability.
transferase Higher enzymatic activity resulting in lower
PFC dopamine levels.
CHNRA 15q14 locus of the alpha-7-nicotinic receptor gene
Genes and phenotypes in
Gene
Schizophrenia
Mechanism
DISC1 Sustained attention and working memory
Disruption in Sz deficits in schizophrenic families
DTNNBP1 Early visual processing deficits, lower
Dystrobrevin binding spatial working memory performance.
protein 1 Influence general cognitive ability
NRG1 Moderate impact of this gene on sustained
Neuroregulin attention and working memory in the
general population
COMT Increased Val108/158Met allele in
Catechol O Methyl schizophrenia patients and in non-affected
transferase relatives. Association of the Val-allele for
P50 sensory gating and schizotypal
personality traits

BDNF Val66Met polymorphism connected with


early phases of information processing in
schizophrenia and with verbal memory in
schizophrenia and healthy controls groups.
Putative Genetic
Pathways
The risk alleles” account for small amount of the
total population risk.
Many of the genes overlap with the risk for
Bipolar Disorder (1q, 2p, 10p, 13q, 18p and
22q).

Other risk pathways:


De novo mutations in paternal allelles
Copy number variations
Gene-environment interactions
Gene expression modification
Gray and Roth, 2007
Risk for schizophrenia
Maternal medical conditions:
pre-eclampsia, diabetes Childhood /
Prenatal Exposures: adolescence
infection (influenza, rubella) Cannabis
Malnutrition
stress (war, flood)
Traumatic brain
Rh incompatibility injury
Environmental Exposures: Trauma, loss,
Urban birth stress
Migration
Lead Exposure Obstetric conditions:
especially hypoxia
low birth weight
preterm birth
Family history:
synaptic element
Advancing paternal age explains
25% of schizophrenia risk

RR

Malaspina et al 2001
Examples of gene –
environment interaction
COMT (the catechol-O-methyl transferase Val158Met
polymorphism) moderates the onset of psychosis in
response to stress and to cannabis use
Neurodevelopment genes, such as AKT1 (serine-threonine
kinase), BDNF (brain-derived neurotrophic factor),
DTNBP1 (dysbindin) and GRM3 (metabotropic glutamate
receptor increase the incidence with perinatal obstetric
complications.
Neurocognitive deficits (also considered to be
endophenotypes) are linked risk alleles for schizophrenia
including COMT, neuregulin (NRG1), BDNF, Disrupted-In-
Schizophrenia 1 (DISC1) and dysbindin.
Cognitive improvement during rehabilitation therapy is
related to COMT (Val158Met) polymorphism.
Biomarkers of genetic vulnerability:
Endophenotypes
1. Smooth
pursuit eye
movements in
schizophrenia
show saccadic
intrusions

2. Auditory Evoked
Potentials: (Gating.) The
response to 1st click
(conditioning) is larger
than to the 2nd (test)
click; in schizophrenia
there is less inhibition of
the response to 2nd
stimulus
3. OTHERS: smell identification, continuous performance test -
attention, working memory, brain activation, soft neurological
signs, Wisconsin card sort test…
BrainVolume :
Larger fluid spaces, diffuse loss of gray matter
Reduced hippocampal volume
smaller frontal and temporal lobes
reduced corpus callosum thickness
Loss of normal assymetry

Normal Schizophrenia

Large ventricles and loss of cortex


Abnormal cellular patterns & glial Loss

Theory of Increased
synaptic “pruning”
Schizophrenia
Normal

Increased neuron density,


decreased synapse density,
smaller neurons
Abnormal brain function
Dorsolateral prefrontal cortex
Working memory as an index
for negative symptoms Superior temporal gyrus
Brain regions
activated
during auditory
hallucinations

Thalamus
The hippocampus is a complex circuit of
subregions that differ in neuronal populations
and susceptibility to different pathologies
Rate of gray matter loss in adolescence

Normal Schizophrenia
Adolescents
Mental disorders are brain disorders:
Loss of gray matter in childhood
schizophrenia
Dopamine theory of
schizophrenia: increased DA 
Psychosis

• All conventional antipsychotics block


the dopamine D2 receptor

• Conventional antipsychotic potency is


directly proportional to dopamine
receptor binding
• Dopamine enhancing drugs can induce
psychosis (e.g., chronic amphetamine
use)
Dopamine theory of psychosis
too much dopamine in psychosis

Psychosis Healthy

D2
blocking
drugs

Excess DA increases the salience of irrelevant stimuli


Roles for other neurotransmitters
NMDA Glutamate Serotonin hypothesis
Hypofunction
LSD is psychotogenic
PCP ( NMDA antagonist)
causes a schizophrenia Serotonin blockage seen in
like syndrome. some atypical drugs.

Glutamate agonists Autopsy results show


reduced 5HT2 receptors
( e.g. glycine) may be in the prefrontal cortex,
modestly therapeutic
(But PET studies of living
NMDA over activity schizophrenics do not
confirm these findings)
 excessive excitatory in
the fontal cortex.

 Negative Symptoms
Evidence for glutaminergic
abnormality in schizophrenia
Decreased expression of hippocampal non- ++
NMDA receptors
Increased cortical expression of some NMDA ++
receptor subunits
Increased glutamate reuptake in frontal cortex +

Decreased cortical glutamate release +

Altered concentrations of glutamate and +/–


metabolites
Schizophrenia is a
syndrome

SUBTYPES? ETIOLOGIES?

Deficit / nondeficit Genes


Paranoid/ nonparanoid Family factors
Kraepelinian/ non- Cannabis
Familial/ sporadic prenatal malnutrition
Early onset / late onset obstetric complications..
Acute onset/ insidious onset neurotransmitters..
Medication responder/ non- late adolescent exposure
Poor premorbid function/ good neurodevelopment genes
infectious agents
brain injury
Overlap Between
Schizophrenia and Bipolar
Mood Disorders
Symptoms, treatments, genes,
Environmental exposures
• Season of Birth
• Urban birth
• Prenatal infections
• Prenatal malnutrition.
• Obstetric complications
• Low birthweight and Preterm birth
Evidence for a developmental origin
Neuromotor Abnormalities in Infancy and
Childhood:
Delayed milestones, more soft neurological
signs, speech problems and clumsiness at age
7 and 11years.
Behavioral Findings in Childhood:
Isolated play at ages 4 and 6, social anxiety in
teens.
Premorbid Cognitive Limitations:
Lower IQ, attention deficit, poor school
performance.
Congenital Anomalies:
More minor physical anomalies, dermatoglyphic
findings, craniofacial abnormalities.
Adolescents
use less
prefrontal
cortex than
adults to read
emotion

Adults
Natural History of Schizophrenia
Stages of Illness Progression

Premorbid Prodrome
Deterioration Residual
Phase
Psychosis
More symptoms
Higher Function

Gestation/Birth
10 20 30 40 50
Puberty
Age in Years
Disease Progression & Treatment Goals
Constitutional
Healthy
Vulnerability

Prodromal Recovery
State

Psychosis Remission

Deterioration
“It Seems the Fertility Clock Ticks for Men, Too”

February 27, 2007