Sam-Early-Onset-Schizophrenia-2014

Report
EARLY-ONSET
SCHIZOPHRENIA
Samuel J. Eckrich, M.S.
Child Psychopathology
University of Central Florida
FAMOUS SCHIZOPHRENICS
HISTORY OF PSYCHOSIS
Trephination
• as early as 3,000-10,000 BC
• Incas (1350 AD) had 80% survival rate
• Emil Kraepelin (1893): Two types of psychosis- manic depressive and
dementia praecox.
• Eugen Bleuler (1908) coined the term, “schizophrenia.”
• Kurt Schneider (1950s): 1st rank symptoms: Delusions and hallucinations
• Included in all versions of DSMs
• Some Notable changes in the DSM-V
CHANGES IN DSM-V
1) Moved from categorical to spectrum approach:
“Schizophrenia Spectrum and Other Psychotic Disorders”
2) Now includes the following disorders (Table 1):
TABLE 1: DSM-V SZ SPECTRUM AND
OTHER PSYCHOTIC DISORDERS.
Bhati, 2012
CHANGES IN DSM-V
1) Moved from categorical to spectrum approach:
“Schizophrenia Spectrum and Other Psychotic Disorders
2) Now includes the following disorders (Table 1):
3) Eliminated subtypes of schizophrenia: paranoid, disorganized,
catatonic, undifferentiated, and residual
Bhati, 2012
DIAGNOSTIC CRITERIA FOR SCHIZOPHRENIA
ASSOCIATED FEATURES

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Inappropriate affect (laughing without stimulus)
Dysphoric mood (anxiety, depression, sleep disturbance)
Lack of interest in eating
Somatic concerns (depersonalization, derealization)
Cognitive deficits (declaritive and working memory,
language, executive fx, processing speed)
Sensory processing, inhibitory capacity, and attention
Social Cognition deficits (inferring intentions of others)
Anosognosia (lack of insight or awareness of illness)
DSM-V’S RISK FACTORS

Genetic and Physiological (Miller et al. 2011)
Conferred by a spectrum of “risk” alleles, common and
rare, each contributing a small fraction of total
variance.
 Hypoxia
 Greater paternal age
 Prenatal/perinatal adversity, stress, infection,
malnutrition, maternal diabetes


Environmental (Brown, 2011)
Season of birth: late winter/early spring
 Urban environment

DSM-V INFORMED MODEL
Genetics
Positive Symptoms
Negative Symptoms
Cognitive Decline
Prenatal Stress,
Hypoxia,
Paternal age
Environment:
Birth Order
and Urban
Schizophrenia
SCHIZOPHRENIA IN CHILDREN AND
ADOLESCENTS

Definitions and Classifications

Very-early-onset (VEOS), beginning before 13 yrs. old.

Early-onset (EOS), beginning before 18 yrs. old.

Childhood-onset schizophrenia (COS) or “prepubertal” yet
still defined as 12 yrs. or younger, not developmental age.

Adolescent-onset schizophrenia (AOS) between 13-17 yrs.
* Not incorporated into DSM-V
Werry et al., 1991
PREVALENCE

Remained stable over past 50 yrs and occurs similarly across
different countries and cultures (Hafner et al., 1997)
Remschmidt and Theisen 2011

10-18% of all Sz arise before age 18 and 1% before 10yrs old.

42% occur between 21-30.

66% between 20-40.
SEX DIFFERENCES/ONSET

About equally represented among children and
adolescents however some studies:

Under 13 and 15-19 yr. old boys develop Sz more
frequently (Hafner et al., 2007)

More frequent in girls 13-15 (Mehler-wex et al., 2004).

Age of onset: Peaks in early-mid 20s for males, later
20s/ for females.

Females more likely to have late onset (post 55yrs)

Males generally worse premorbid adjustment, lower
educational achievement, more prominent negative
symptoms and cognitive impairment, and in general a
worse outcome (Alvarez-Jimenez et al., 2012).
CLINICAL PRESENTATION OF POSITIVE
SYMPTOMS IN EOS

Hallucinations
Auditory (commands, threats, laughter, humming, whistling)
 Visual, olfactory, gustatory, and tactile are rare, but more
common in COS

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Delusions
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Ideas of reference
Belief of persecution
Bodily change
Delusions of control
Systematized delusions are very rare
Thought distortions
Insertions, breaks and interpolations in train of thought
 Vague and incoherent thinking that is not expressed well.

CLINICAL PRESENTATION OF NEGATIVE
SYMPTOMS IN EOS

Speech
Logorrhea or general paucity of speech
 Perseverations and stereotypies
 Echolalia
 Neologism

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Social functioning


Withdrawal
Emotional manifestations
Blunted affect, apathetic,
 Irritable, fearful, suspicious
 Incongruent emotional responses

OTHER CLINICAL PRESENTATIONS IN EOS
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Motor disturbances
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Clumsiness
Catatonia
Bizarre postures/movements (e.g. stereotypies of fingers)
Rituals
One study found very high incidences of
hallucinations across all modalities in COS (David et al., 2011)
95% Auditory, 80% Visual, 61% tactile, 30% olfactory
 Tactile and olf. only occurred in those with visual
 Visual was associated with greater impairment/worse
overall brain functioning.

*Manifestations often occur long before initial hospitalization
VIDEO
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
https://www.youtube.com/watch?v=UTUMt05_nC
I
Jani
DIFFERENTIAL DIAGNOSIS IN EOS


Difficult.
DSM-V:
Delusions and hallucinations are usually less elaborate
and must be distinguished from normal fantasy play.
 Disorganized speech and behavior commonly occurs in
other disorders (See Table 3).

ETIOLOGY
1) Genetic factors
• Heritability
• Candidate gene regions
2) Neurobiological factors
•
•
Brain morphology
Biochemical
3) Neuropsychological factors
•
•
•
•
Cognitive Impairment
Neurointegrative deficits
Attention deficits
Communication deficits
GENETICS
More overlap
with COS than
Adult-onset
Arsanow, 2013
A FEW PROTEIN TARGETS


Genes scattered across all but 8 chromosomes have been
implicated
Most important:

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Neuregulin 1: NMDA, GABA, & ACh receptors
Dysbindin: synaptic plasticity (esp. NMDAR)
Catechol-O-methyl transferase: DA metabolism
G72: regulates glutamatergic activity
Others: myelination, glial function
Paternal age thought to have an impact
DISRUPTED IN SCHIZOPHRENIA-1 GENE
(DISC-1)

Expressed in forebrain. Affects cell growth,
movement, positioning, and transport.
*Animals that expressed a mutated DISC-1
gene (tg) had significantly larger Lateral
Ventricle volume at neo-natal stages than
those who didn’t express the gene.
Hikida et al., 2007
EXPRESSION PATTERN OF EXOGENOUS DN-DISC1


Exogenous DN-DISC1 is preferentially expressed in neonatal stages rather than in adulthood
DISC1 expression naturally occurs in wild-type (wt) mice
ENLARGED VENTRICLES IN HUMANS
OTHER NEUROMORPHOLOGICAL DIFFERENCES
Pyramidal cell organization in the hippocampus
PYRAMIDAL CELL ORGANIZATION IN
HIPPOCAMPUS
MORPHOLOGICAL DIFFERENCES IN
ADOLESCENTS WITH SZ
1) Enlarged lateral
ventricles
1) Reduced gray
matter
2) Prefrontal
connectivity
(DLPFC, VMPFC)
3) Decreased
hippocampal
volume
4) Decreased
cerebellar volume
ETIOLOGY
1) Genetic factors
• Heritability
• Candidate gene regions
2) Neurobiological factors
•
•
Brain morphology
Biochemical
3) Neuropsychological factors
•
•
•
•
Cognitive Impairment
Neurointegrative deficits
Attention deficits
Communication deficits
BIOCHEMICAL FACTORS


Three main hypotheses: Dopamine (DA),
Serotonin (5-HT), and glutamate.
Evidence for Dopamine Hypothesis:

Amphetamines
increase paranoia, delusions,
auditory hallucinations and exacerbate Sz symptoms

DA antagonists (chlorpromazine, thorazine, other
typical antipsychotics) alleviate the positive
symptoms.

Schizophrenics had ~twice as many D2 receptors
occupied as normal (Meyer-Lindenberg et al., 2002)
5-HT AND GLUTAMATE HYPOTHESES



Atypical antipsychotics (clozapine, olanzapine,
etc.,) block 5-HT2A receptors and increase DA!
Negative symptoms were at first thought to be
attenuated by AAs.
Glutamate:
PCP, Mk-801, Ketamine are NMDAr antagonists
(decreases glutamate) cause hallucinations, paranoia,
and depersonalization.
 Emulates chronic cognitive dysfunction and
hypofrontality found in those with Sz.
 So why not give glutamate agonist?

PROBLEMS WITH BIOCHEMICAL HYPOTHESES
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Approximately normal levels of DA in
schizophrenics (Jaskiw & Weinberger, 1991).
Antipsychotic drugs block DA synapses within
minutes, but beneficial effects build up over 2 – 3
weeks.
Most have very complicated mechanisms of actions:
increasing D1 receptors while decreasing D2rs.,
tinkering with one of the 20 5-HT receptors, or
combining.
Dark secret…no one really knows what is going on.
ETIOLOGY
1) Genetic factors
• Heritability
• Candidate gene regions
2) Neurobiological factors
•
•
Brain morphology
Biochemical
3) Neuropsychological factors
•
•
•
•
Cognitive Impairment
Neurointegrative deficits
Attention deficits
Communication deficits
SUMMARY OF GENETIC AND
NEUROBIOLOGICAL FACTORS
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Genetics obviously play a role, but it isn’t
incredibly robust.
Certain genes like DISC-1 can contribute to
neuroanatomical differences at a young age.
Large volume differences in Lateral Ventricle.
Structural differences in frontal cortex,
hippocampus, and cerebellum.
DA, 5-HT, and glutamate hypotheses may
account for positive, negative, and cognitive
symptoms, respectively.
ETIOLOGY
1) Genetic factors
• Heritability
• Candidate gene regions
2) Neurobiological factors
•
•
Brain morphology
Biochemical
3) Neuropsychological factors
•
•
•
•
Cognitive Impairment
Neurointegrative deficits
Attention deficits
Communication deficits
COGNITIVE IMPAIRMENT SPECIFIC TO
EOS
COGNITION TESTS COMMONLY USED IN
EOS
* A big problem with using consistent measurements:
National Institute of Mental Health MATRICS
(Measurement and Treatment Research to Improve
Cognition in Schizophrenia) Dr. Green at UCLA is a
world leader in Sz research
Frangou 2013
NEUROCOGNITIVE TESTS IN CHILDREN
WITH ANTECEDENTS TO SZ

Meta-analysis of premorbid IQ measurements
(assessed in childhood and later developed Sz)

~ 8 IQ points lower than TD individuals who did not
go on to develop psychotic symptoms (dES = .55).
(Woodberry et al., 2008)

In one study by Cullen et al., children (9-12yrs.)
At least one 1 “psychotic-like” episode
 Social, emotional, behavioral problems
 Early speech and/or motor developmental delays

*Mean of all
neurocog. tests: dES
= .52
•Effect Sizes:
GI = .55; VM = .54;
WM = .95; EF-I = .66
Fig. 1 Scatterplots indicating the distribution of z-scores obtained on each neurocognitive domain
by children presenting putative antecedents of schizophrenia (ASz) and by typically-developing
children (TD) without the antecedents.
Cullen et al., 2010
TRAJECTORY OF COGNITIVE DYSFUNCTION
IN EOS
Moving from premorbid to syndromal



EOS had 1-1.5 SD worse on IQ tests compared to
Adult onset.
Big picture: Earlier presentation of symptoms, the
more dysfunction later in life.
Some areas of cognitive
functioning found to be
more pervasive. (Frangou
2013).
ETIOLOGY OF COGNITIVE DYSFUNCTION:
HYPOFRONTALITY/CONNECTIVITY
Kyriakopoulos et al., 2012

NEURAL UNDERPINNINGS CONCLUSION
During adolescence, significant remodeling and
strengthening of neural circuits subserving
higher cognitive functions.
 Functional imaging studies suggest a progressive
deviance in prefrontal recruitment from
adolescents to adulthood
 These functional changes along with anatomic
differences in EOS show progressive loss in
prefrontal gray volume and white matter
integrity throughout adolescence and into young
adulthood.

LONGITUDINAL STUDIES/PROGNOSIS

Arsanow et al., 1999
Followed 18 children diagnosed with Sz
 Two follow-up assessments using K-SADS, K-SKIPS, and
GAS at 1-7 years and 11-18 yrs from initial diagnosis.

A SYSTEMATIC REVIEW OF EOS
PROGNOSIS
Global Function Scale, Global Assessment of Functioning,
Children’s Global Assessment Scale, Global Assessment
Scale, Study-Specific Functioning.
ENVIRONMENTAL RISK FACTORS

Childhood environment
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Dunedin study
atypical mother-child interactions (OR = 2.65, CI
1.2-5.6)
Physical/sexual abuse (Diathesis stress model)
Drug use/abuse esp. Psychostimulants and Cannabis (RR = 2.4)
Perinatal
Pooled OR = 1.07
 Maternal malnutrition (OR = 2.9), stress, diabetes, smoking,


Poor nutrition = more Sz
Season of birth

More plausible: Influenza, viruses, parasites

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Dutch Hunger Winter studies
Herpes simplex type 2, taxoplama gondii
Obstetric complications

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Complications of pregnancy
Fetal growth and development
Complications of delivery
Hypoxia (RR = 2-3)
Very small
effect sizes and
OR < 2.
Dean and Murray, 2005
ENVIRONMENTAL RISK CONT.

Migration
Especially African-Caribbean in the UK
 Higher incidence rates (1.7-13.2) when the group’s
position in society was considered disadvantaged.


Urbanicity
One of the most consistent findings: 38-67% more
likely to develop schizophrenia (Pederson et al., 2004).
 Dose-response fashion (causality?)
 Several validity/conceptual problems
 Most likely due to social isolation

TREATMENT


None listed in Division 53
Pharmacological approach is generally the first
line of defense.

Second generation antipsychotics (atypical) are primarily
antiserotonergic and dopamine altering. (e.g. clozapine,
aripiprizole, resperidone, quietiapine, olanzapine)


Originally thought to decrease positive and negative symptoms
 Extrapyramidal symptoms are less common
 Weight gain is common.
First generation antipsychotics (typical) are
antidopaminergic (e.g. Haloperidol, Chlorpromazine)

Primarily work to decrease positive symptoms
 Tardive dyskinesia is a common side-effect
ANTIPSYCHOTIC INTERVENTION IN
ADOLESCENT OS: A REVIEW
Very few studies. Generally use Atypical, only
aripiprozole is FDA approved.
 Cochrane review looked at 13 RCTs with over
1,100 participants. Global state, mental state,
adverse effects (weight gain, sedation, motor
effects), drop out rate were assessed. (Datta et al., 2013)

Atypical vs. Placebo: No difference (more
dropped out in the placebo group).
 No difference between AAs, except aripiprozole
had less weight gain.
 No difference in AAs vs. TAs.
 Need more studies!

REVIEW ONLY LOOKING AT PANSS (POSITIVE
AND NEGATIVE SYMPTOM SCALE) SCORES AGES
13-17.

Shimmelmann et al., 2013
CLINICAL ANTIPSYCHOTIC TRIALS OF
INTERVENTION EFFECTIVENESS (CATIE)
Big recent (2013) finding from CATIE. No
difference between AAs and TAs.
 Antipsychotic medications are more effective
than placebo at reducing positive symptoms and
relapse rates.


Large meta-analyses studies show approx. 25% with
AAs relapsed vs. 65% on placebo (Gilbert et al., 1995; Leucht et al.,
2012).
No change in cognitive functioning or negative
symptoms
 Quality of life not improved

PSYCHOSOCIAL TREATMENT


Very few studies for EOS
Shimmelman et al., 2013 review
*No one treatment
is more effective
than another.
*Most experts
suggest combined
approach
* Family
intervention, social,
and problem solving
skills are probably
efficacious.
NEW TREATMENT APPROACHES

Targeting cognitive and negative symptoms.

Metabotropic glutamate receptors (mGluRs), Nacetyl-cystein, phosphodiesterase inhibitors,
modafinil, Omega-3, oxytocin.

Depot shots to increase adherence.

Psychoeducation in the community.

Early identification and intervention in
prodromal stages.
ALTERNATIVE EARLY DIAGNOSTIC
TOOLS?
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Scratch-n-sniff: common odors (pizza,
smoke, orange, bubble gum, gasoline,
chocolate, clove, wintergreen, etc.
Olfaction is processed in frontal and
temporal lobes
Can predict onset and severity
80+% Sz patients show deficit vs 10-15% in
general population
Some data suggest M Sz are particularly
poor at emotional olfactory memories
Venule Caliber
Red Light Effect
DSM-V INFORMED MODEL
Genetics
Positive Symptoms
Negative Symptoms
Cognitive Decline
Prenatal Stress,
Hypoxia,
Paternal age
Environment:
Birth Order
and Urban
Schizophrenia
Genetics:
1st degree
relative,
paternal age
GABA,
glutamate, DA
Perinatal:
Stress,
nutrition,
influenza
Obstetric:
hypoxia
Asymptomatic
Environment:
urbanicity,
abuse,
parasites,
cannabis, social
isolation
Neuroanatomical
chemical:
hypofrontality,
gray matter,
hippocampus, DA,
glutamate
Cognitive
Dysfunction
Prodromal
A New Model
Antipsychotics
Positive
Symptoms
Negative Symptoms
1st Psychotic Episode
Fully Symptomatic
THE END
SPECIFIERS
EXECUTIVE FUNCTIONING

Well-established in adults. Stroop and Wisconsin
Card Sort Test (WCST)
COGNITIVE IMPAIRMENT SPECIFIC TO
EOS

General intellectual ability (IQ)

Executive Functioning



Especially working memory (d = .78-.98), Attention (d =
1.47), rule discovery/perseveration (d = .7).
Processing Speed (d = .66). Earliest detectable
difference compared to HC.
Associated impairments: verbal memory and
learning (d = .68-.96), problem solving (d = .5)
TRAJECTORY OF COGNITIVE DYSFUNCTION
IN EOS


Big picture: Earlier presentation of symptoms, the
more dysfunction later in life.
Moving from premorbid to syndromal
EOS had 1-1.5 SD worse on IQ tests compared to Adult
onset
 Processing speed (Digit Symbol): Two SDs worse
compared to HCs in one study() and AOS ES = .66 ()
 Working Memory (Digit Span and 1-back) EOS compared
to HC

ELECTROPHYSIOLOGICAL FACTORS




Differences in skin conductance
Slow habituation
Evoked Potentials – debatable.
Gamma Band asynchrony (40-70 hz)

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