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

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 SymptomsNegative

SymptomsCognitive 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)

10-18% of all Sz arise before age 18 and 1% before 10yrs old.

42% occur between 21-30.

66% between 20-40.

Remschmidt and Theisen 2011

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 Delusions

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

Social functioning Withdrawal

Emotional manifestations Blunted affect, apathetic, Irritable, fearful, suspicious Incongruent emotional responses

OTHER CLINICAL PRESENTATIONS IN EOS

Motor disturbances 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

https://www.youtube.com/watch?v=UTUMt05_nCI

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: 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.

Hikida et al., 2007

*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.

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

2) Reduced gray matter

3) Prefrontal connectivity (DLPFC, VMPFC)

4) Decreased hippocampal volume

5) 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

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

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

Frangou 2013* 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

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

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

*Mean of all neurocog. tests: dES = .52

•Effect Sizes: GI = .55; VM = .54; WM = .95; EF-I = .66

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 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 Maternal malnutrition (OR = 2.9), stress, diabetes, smoking,

Dutch Hunger Winter studies Poor nutrition = more Sz

Season of birth More plausible: Influenza, viruses, parasites

Herpes simplex type 2, taxoplama gondii

Obstetric complications Complications of pregnancy Fetal growth and development Complications of delivery Hypoxia (RR = 2-3)

Very small effect sizes and OR < 2.

Pooled OR = 1.07

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), N-

acetyl-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?

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 SymptomsNegative

SymptomsCognitive Decline

Prenatal Stress, Hypoxia,

Paternal age

Environment:Birth Order and Urban

Schizophrenia

Genetics: 1st degree relative,

paternal ageGABA,

glutamate, DA

Perinatal:Stress,

nutrition, influenza

Obstetric:hypoxia

Environment: urbanicity,

abuse, parasites, cannabis,

social isolation Antipsychotics

Cognitive Dysfunction

Positive Symptoms

Negative Symptoms

Neuroanatomical chemical:

hypofrontality, gray matter,

hippocampus, DA, glutamate

Asymptomatic Prodromal 1st Psychotic Episode Fully Symptomatic

A New Model

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)