Early-Onset
Schizophrenia
Kirran Bakhshi
Child Psychopathology
November 6, 2013
What is…
Schizophrenia?
“Defined by abnormalities in one or more of the following
five domains: delusions, hallucinations, disorganized
thinking/speech, disorganized/abnormal motor
behaviour, and negative symptoms” (DSM-V, American
Psychiatric Association, 2013)
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DSM-V
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Criteria A
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Need 2 or more of the following, present for a significant
portion of time for a 1 month period (or less, if
successfully treated)
One of the 2 must be (1), or (2), or (3)
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Criteria A: Delusions (1)
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Fixed beliefs that are not amenable to change in light of
conflicting evidence
May include variety of themes:
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Persecutory: belief that one will be harmed by others
Referential: belief that certain gestures directed at oneself
Grandiose: belief that self possesses extraordinary abilities
Erotomanic: [false] belief that another person is in love w/ self
Nihilistic: belief that a major catastrophe will occur
Somatic: preoccupations w/ health & organ function
Specifier: bizarre [if delusions are clearly implausible and not
understandable to same-culture peers, and do not derive from
ordinary life experiences]
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ie. delusions that express loss of control over mind/body

thought withdrawal,
thoughtofinsertion,
delusions of control
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Central Florida
Criteria A: Hallucinations (2)
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Perception-like experiences that occur w/o external
stimulus
Vivid and clear, w/ full force and impact of normal
perceptions; not under voluntary control
May occur in any sensory modality, but auditory are
most common
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Distinct from individual’s own thoughts
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Criteria A: Disorganized speech (3)
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Substantially impairs effective communication
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Typically inferred from individual’s speech
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Presentation:
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loose associations (switching from topic to topic
tangentiality
incoherence (‘word salad’)
AKA ‘formal thought disorder’
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Criteria A: Disorganized behaviour
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May manifest in diff ways (ie. childlike ‘silliness’ to
unpredictable agitation)
Problems can be seen in any form of goal-directed
behaviour
Leads to difficulties in performing activities of daily life
Note: catatonia (marked decrease in reactivity to
environment)
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Ranges from negativism (resistance to instructions) to mutism &
stupor (complete lack of verbal/motor responses, maintaining
rigid posture)
May include catatonic excitement (purposeless/excessive motor
activity, w/o obvious cause), repeated stereotyped movements,
staring, grimacing, echoing of speech
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Criteria A: Negative Symptoms

Account for substantial portion of morbidity associated w/
SZ
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Diminished emotional expression: face, eyes, speech,
hand/head/face
Avolition: decrease in motivated self-initiated purposeful
activities
Can also include alogia (diminished speech output),
anhedonia (decreased inability to experience pleasure),
asociality (lack of interest in social interactions)
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Criteria B-F
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B: level of functioning in one or more major areas is
markedly below level prior to onset (EOS: failure to
reach expected level of functioning)
C: Continuous signs of disturbance for at least 6 mos, w/
at least 1 mo of active symptoms
D: Schizoaffective & MDD/BPD w/ psychotic features
ruled out
E: not due to substance or other medical condition
F: if history of ASD: only diagnose SZ if prominent
delusions or hallucinations present, in addition to other
symptoms
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Clinical manifestation
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Range of cognitive, behavioural & emotional dysfunction
NO SINGLE SYMPTOM IS PATHOGNOMIC
Heterogeneous clinical presentation = constellation of
signs and symptoms
Prodromal symptoms often precede active phase, &
residual symptoms may follow
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Commonly negative symptoms; can be severe
Mood symptoms/episodes common
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Assessment of these critical for making correct diagnosis
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Associated features: MANY
Deficits in executive
function
Inappropriate affect
Lack of insight
(anosognosia)
Dysphoric mood
Social cognition deficits
Somatic concerns
Derealization
Disturbed sleeping pattern
Abnormal sensory
processing/integration
Abnormal inhibitory capacity
Depersonalization
Impairments in motor coordination
Cognitive deficits
Minor
physical
anomalies
Differences in
cellular architecture,
WM connectivity, GM
volume
Reduced
overall brain
volume
Reductions in attention
Anxiety/phobias
Lack of interest in eating
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Prevalence & gender
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Lifetime prevalence: 0.3-0.7%
Variation by ethnicity, country, geographic origin
Age of onset tends to be slightly lower in females,
although do have a second mid-life peak
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General incidence also slightly lower
Symptoms = more affect-laden, more psychotic symptoms,
worsening of psychotic symptoms later in life
Less frequent negative symptoms & disorganization
Social functioning better preserved
Males: worse premorbid adjustment, lower educational
achievement, more prominent negative symptoms &
cognitive impairment  generally worse outcome
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Onset & course I
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Typical onset b/w late teens and early 30s (we are not out of the
woods yet!)
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Peak: males: early-mid 20s;
females: late-20s
Onset can be abrupt or
insidious (majority = gradual
development of variety of
symptoms)
Earlier age of onset
generally = worse prognosis
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Onset & course II
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Impaired cognition common; present during
development, precede SZ  stable cognitive
impairments during adulthood
Predictors of course/outcome  UNEXPLAINED
Course favourable in ~20%
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Most still require (in)formal daily living supports
Many remain chronically ill: some w/ exacerbations &
remissions, some with progressive deterioration
Psychotic symptoms tend to diminish over life course
Negative symptoms tend to be more persistent
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EOS: Early-onset schizophrenia
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Essential features are the same
However, more difficult to make diagnosis
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Delusions/hallucinations may be less elaborate
Visual hallucinations more common  need to be distinguished
from normal fantasy play
Disorganized speech/behaviour occurs in many other childhood
disorders
Tend to resemble poor-outcome adult cases: gradual
onset & prominent negative symptoms
Those who receive Dx=SZ more likely to have
experienced nonspecific emotional behavioural
disturbances & psychopathology, intellectual & language
alterations, and subtle
motor delays
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Risk factors
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Environmental: season of birth, urban environment,
(specific) minority ethnic groups
Genetic/physiological: strong contribution for genetic
factors
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Although most individuals w/ SZ have no family history of
psychosis
Liability conferred by spectrum of risk alleles (non-pathognomic)
Pregnancy & birth complications, greater paternal age
Other prenatal/perinatal adversities: stress, infection,
malnutrition, maternal diabetes, other medical conditions
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However, vast majority of those w/ these risk factors do not develop
SZ
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A note on culture
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Important to consider the effect of culture, esp when
individual & clinician do not share the same background
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Why might this be?
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Functional consequences
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Suicide: approx 5-6% die by suicide, ~20% attempt,
many more have ideation, & risk remains high over
lifetime
SZ associated w/ significant social and occupational
dysfunction
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Educational progress & maintaining employment frequently
impaired
Employed at lower level than parents, may not marry or have
limited social contact
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Differential I
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MDD/BPD w/ psychotic features: depends on temporal
relationship b/w mood disturbance & psychosis, and on
severity of mood symptoms
Schizoaffective: mood episode occurs concurrently w/
active psychotic symptoms, and present for majority of
total duration of active periods
Schizophreniform, brief psychotic disorder: shorter
duration than SZ
Delusional disorder: absence of other characteristic SZ
symptoms
Schizotypal PD: presence of subthreshold symptoms
associated w/ PD
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Differential II
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OCD/body dysmorphic disorder: presence of
prominent obsessions, compulsions, preoccupations w/
appearance/body odour, hoarding, body-focused
repetitive behaviours [these not seen in SZ]
PTSD: presence of traumatic event and characteristic
symptoms related to reliving event [not seen in SZ]
ASD: presence of deficiencies in social interaction w/
repetitive & restricted behaviours, and other cognitive &
communication deficits [not seen to this degree in SZ]
Other mental disorders assoc w psychotic episode:
psychotic episode must be persistent, not attributable to
substance/medical condition; impt to look at temporal
relationship
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Comorbidity
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Substance-abuse disorders: high
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Over half use tobacco
Anxiety disorders (OCD, panic disorder)
Life expectancy = reduced  associated medical
conditions
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Weight gain, diabetes, metabolic syndrome, cardiovascular &
pulmonary disease
Poor engagement in health maintenance behaviours 
increases risk of chronic disease
Medications, lifestyle, cigarette smoking, diet
May be a shared vulnerability for psychosis and medical
disorders
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Video!
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Four patients with schizophrenia:
https://www.youtube.com/watch?v=bWaFqw8XnpA
What’s it like to experience schizophrenia symptoms:
http://www.wimp.com/schizophrenicsymptoms/
What’s schizophrenia like? TEDTalk
http://www.wimp.com/schizophrenicsymptoms/
Also: Jani, Dx w/ SZ at age 6 (on Oprah, Dr Phil,
Discovery Health)
Many videos of Elyn Saks (TEDTalk, interviews, etc)
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Model: DSM-V
Genetic/physiologi
cal risk factors
Environmental risk factors
• genes
• birth complications
Gender
• age of onset
Associated features
•
•
•
•
inappropriate affect
cognitive deficits
depersonalization
ETC
Culture
Core features
• Criteria A
• cognitive, behavioural,
emotional dysfunctions
Functional
consequences
• sig social & occupational
impairment
Comorbidity
• substance abuse (tobacco)
• anxiety
• medical issues (CV, weight
gain, chronic disease, lifestyle,
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etc)
Literature
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What is going to happen now:
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I am not going to talk about everything there is to know
about SZ: we would be here for months
I will endeavor to give a general overview of SZ as we
know it today, & touch on major topics
We will discuss differences in EOS
There will be some slides on brain stuff
And then my model
If we have time, we can watch another video
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Basics
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First conceptualized by Emil Kraepelin as ‘dementia
praecox’
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Research at every level of organization:
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Macro: whole brain/body
Modular: whole units (lobes)
Networks: whole systems (default mode network)
Cellular: neuron organization (cortical layers)
Molecular: specific parts of the cell (receptors)
Genetic: specific genes on specific chromosomes (allelic
mutations)
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Theories
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Obviously, many and varied:
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Neurodevelopmental
Progressive
Progressive neurodevelopmental
DA
Glutamatergic
Psychoanalytic
Dysconnectivity
Inflammatory
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Neurodevelopmental theory
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Synthesized by Weinberger in 1987
Posits that SZ arises as a process of aberrant
neurodevelopmental processes
There is an initial lesion/insult in the brain, which is
unmasked by brain changes at the time of sexual
maturation [ie. puberty]
This affects later neuroplastic events
Support comes from studies of changes in
cytoarchitecture and cerebral asymmetry, as well as
studies looking at first episode and those at high risk
Primary tenet: stability of cognitive function later in
illness, after initial decline
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Genetics
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Heritability estimates reported to be b/w 60-80%
(Schwab & Wildenauer, 2013)
Many genes, mutations, repeats, variants, etc have been
implicated in SZ
Now the field is moving more towards copy number
variants, single nucleotide polymorphisms, association
studies, “deep sequencing”
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CNVs may be more impt in sporadic cases: high frequency of ‘de
novo mutations’
Recent study: Ripke et al, 2013: 22 risk loci, more than 8300
SNPs  32% liability
Genome-wide studies: SZ is polygenic disorder (perhaps
more than 100 genes  listed on next page*)
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Cognition
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Although the DSM lists altered cognition as an
associated feature of SZ, it really is one of the hallmark
symptoms; some (many) even suggest that it should be
listed as part of the diagnostic criteria
Altered cognitive functioning includes problems w/
memory, attention, motor skills, executive function, & IQ
 major source of disability (Pandina et al, 2013)
Better cognitive functioning associated w/ increased
quality of life (Savilla et al, 2008), and may particularly
affect social and employment aspects
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Cognition
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Theory of cognitive reserve:
some people inherently have
larger ‘cushion’ that protects
them from the effects of SZ
(initially developed for AD
research)
IQ at psychosis onset has
been linked to clinical
outcomes (Leeson et al,
2011) and may predict a
more severe course (low or
deteriorated IQ)
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Cognition
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Rajji et al, 2009
Let’s talk about neuro
“Schizophrenia is the graveyard of
neuropathologists” (Plum, 1972)
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Yet SZ is acknowledged by many (or even most) to be a
disorder of neurodevelopment
Researchers have persevered, and now we know quite a
lot about what’s going on in the SZ brain; however, not
nearly enough
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Neuro
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It all started in 1976, with a computerized tomography
study showing that pts w/ SZ have larger ventricles
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Johnstone et al, 1976
Neuro
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Since then, some of the most replicated findings include:
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Increases in ventricular size
Decrease in whole brain volume
Decreases in gray matter volume
Altered connectivity
Altered aging
Changes in neuronal density, organization, type
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Ventricular size
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Kempton et al, 2010
Whole brain volume
Keller et al,
2003
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Gray matter
Yuksel et al,
2012
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Connectivity
Skudlarski et al, 2010
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Aging
van Haren et
al, 2008
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Neuronal changes
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Solomon,
2004
EOS
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Early-onset SZ is generally defined as onset <18 years,
although some define <20
Childhood-onset SZ, which is very early-onset SZ, is
generally <13 (Clemmensen et al, 2012)
Based on a NIMH cohort, incidence of VEOS <0.4%
(Driver et al, 2013)
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VEOS = more severe form: more prominent prepsychotic
developmental disorders, brain abnormalities, genetic risk
factors
specific cohort (n=118): 55%=premorbid academic impairments,
72%=premorbid social/behavioural impairments, 51%=premorbid
language impairments, 44%=premorbid motor impairments,
20%=positive for pervasive developmental disorder
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EOS
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EOS
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A 15-yr FU showed (Ropcke &
Eggers, 2005): full remission
seen in 8%, moderate
outcome in 56% and poor
outcome in 36% (based on
scores from Clinical Global
Impression)
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Mean age of onset 16, +/-1.52,
FU ranged from 10-21 yrs; n=39
Severe impairments of global
social functioning (using Global
Assessment of Social Function)
in 51%
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EOS
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Profile of GM loss in VEOS
(Thompson et al, 2001)
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N=12, mean age=14, onset by age
12
Scanned w/ MRI 3 times at 2 yr
intervals
Earliest deficits in parietal regions,
progressed anteriorly into temporal
lobes and DLPFC
Correlated w/ symptom severity
Mirrored neuromotor, auditory,
visual search and frontal executive
impairments
Controlled for medication, IQ,
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of Central
Florida
replicated separately
in M and
F
EOS
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Thompson et al, 2001:
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EOS
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Neurocognition in EOS (Frangou, 2013)
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EOS
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Neurocognition in EOS (Frangou, 2013)
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EOS
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WM tract integrity (Kyriakopoulos et al, 2008)
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n=19, mean onset=14.77, wrt HC
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EOS
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Brain abnormalities in
EOS (Sowell et al,
2000)
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n=10, mean age
onset=11, age range=716, wrt HC
EOS=larger ventricles,
changes in mid corpus
callosum (WM),
posterior cingulate,
caudate, thalamus
Notice the
difference in
ventricular size
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My model
Genetic/physiolo
gical risk factors
Altered gray matter,
white matter,
lateralization
Environment
• genes
• birth complications
Altered
neurodevelopment
Functional
consequences
• lack of job/social
skills/friends
• homelessness
• decreased life expectancy
(suicide)
• medication side effects
• poor health
Prodrome
Gender
• age of onset
Core features
• Criteria A
• cognitive deficits
• electrophysiological diff
• lack of insight
Culture
Comorbidity
• medical issues (CV, weight gain,
chronic disease, etc)
• other psych conditions
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(depression)
Associated features
• lifestyle factors
• substance abuse (tobacco)
Thank you!
Questions?
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References I
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
Diagram slide 1: http://www.scientificamerican.com/article.cfm?id=new-genetic-model-schi
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders
(5th ed.). Arlington, VA: American Psychiatric Publishing.
Diagram slide 14: http://digital-art-gallery.com/picture/11199
Weinberger, D.R. (1987). Implications of normal brain development for the pathogenesis of
schizophrenia. Arch Gen Psychiatry, 44, 660-669.
Schwab, S. G. & Wildenauer, D. B. (2013). Genetics of psychiatric disorders in the GWAS era: an
update on schizophrenia. Eur Arch Psychiatry Clin Neurosci., 263 (Suppl), 147-154.
Ripke, S. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia.
Nat Genet, 45, 1150-1159.
Pandina, G., Bilder, R., Turkoz, I., & Alphs, L. (2013). Identification of clinically meaningful
relationships among cognition, functionality, and symptoms of subjects with schizophrenia or
schizoaffective disorder. Schizophrenia Research, 143, 312-318.
Savilla, K., Kettler, L., & Galletly, C. (2008). Relationships between cognitive deficits, symptoms
and quality of life in schizophrenia. Aust N Z J Psychiatry, 42, 496-504.
Leeson, V.C., Sharma, P., Harrison, M., Ron, M.A., Barnes, T.R.E., & Joyce, E.M. (2011). IQ
trajectory, cognitive reserve, and clinical outcome following a first episode of psychosis: A 3-year
longitudinal study. Schizophrenia Bulletin, 37, 768-777.
Rajji, T.K., Ismail, Z., & Mulsant, B.H. (2009). Age at onset and cognition in schizophrenia: Metaanalysis. British Journal of Psychiatry, 195, 286-293.
Plum, F. (1972). Prospects for research on schizophrenia. 3. Neurophysiology. Neuropathological
findings. Neuroscie Res Program
Bull, 10,of384-388.
University
Central Florida
References II
12)
13)
14)
15)
16)
17)
18)
19)
20)
Johnstone, E.C., Crow, T.J., Frith, C.D., Husband, J., & Kreel, L. (1976). Cerebral ventricular size
and cognitive impairment in chronic schizophrenia. Lancet, 2, 924-926.
Kempton, M.J., Stahl, D., Williams, S.C.R., & DeLisi, L.E. (2010). Progressive lateral ventricular
enlargement in schizophrenia: A meta‐analysis of longitudinal MRI studies.
Keller, A., Castellanos, F.X., Vaituzis, A.C., Jeffries, N.O., Giedd, J.N., & Rapoport, J.L. (2003).
Progressive loss of cerebellar volume in childhood-onset schizophrenia. Am J Psychiatry, 160,
128-133.
Yuksel, C., McCarthy, J., Shinn, A., Pfaff, D.L., Baker, J.T., Heckers, S., … Ongur, D. (2012).
Gray matter volume in schizophrenia and bipolar disorder with psychotic features.
Schizophrenia Research, 138, 177-182.
Skudlarski, P., Jagannathan, K., Anderson, K., Stevens, M.C., Calhoun, V.D., Skudlarski, B.A.,
…Pearlson, G. (2010). Brain connectivity is not only lower but different in schizophrenia: a
combined anatomical and functional approach. Biol Psychiatry, 68, 61-69.
van Haren, N.E.M., Hulshoff Pol, H.E., Schnack, H.G., Cahn, W., Brans, R., Carati, I., … Kahn,
R.S. (2008). Progressive brain volume loss in schizophrenia over the course of the illness:
Evidence of maturational abnormalities in early adulthood. Biol Psychiatry, 63, 106-113.
Selemon, L.D. (2004). Increased cortical neuronal density in schizophrenia. Am J Psychiatry, 161,
9.
Clemmensen, L., Vernal, D.L., & Steinhausen, H.C. (2012). A systematic review of the long-term
outcome of early onset schizophrenia. BMC Psychiatry, 12, 150-165.
Driver, D. I., Gogtay, N., & Rapoport, J.L. (2013). Childhood onset schizophrenia and early onset
schizophrenia spectrum disorders. Child Adolesc Psychiatr Clin N Am, 22, 539-555.
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References III
21)
22)
23)
24)
25)
Röpcke, B., & Eggers, C. (2005). Early-onset schizophrenia: a 15-year follow-up. Eur Child
Adolesc Psychiatry, 14, 341-350.
Thompson, P.M., Vidal, C., Giedd, J.N., Gochman, P., Blumenthal, J., Nicholson, R., …Rapoport,
J.L. (2001). Mapping adolescent brain change reveals dynamic wave of accelerated gray matter
loss in very early-onset schizophrenia. Proc Natl Acad Sci U.S.A., 98, 11650-11655.
Frangou, S. (2013). Neurocognition in early-onset schizophrenia. Child Adolesc Psychiatr Clin N
Am, 63, 519-523.
Kyriakopoulos, M., Vyas, N.S., Barker, G.J., Chitnis, X.A., & Frangou, S. (2008). A diffusion tensor
imaging study of white matter in early-onset schizophrenia. Biol Psychiatry, 63, 519-523.
Sowell, E.R., Levitt, J., Thompson, P.M., Holmes, C.J., Blanton, R.E., Kornsand, D.S., …Toga,
A.W. (2000). Brain abnormalities in early-onset schizophrenia spectrum disorder observed with
statistical parametric mapping of structural magnetic resonance images. Am J Psychiatry, 157,
1475-1484.
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