Early-Onset Schizophrenia

Early-Onset Schizophrenia

Kirran BakhshiChild Psychopathology

November 6, 2013

University of Central Florida

What is…

“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)

Schizophrenia?


DSM-V


Criteria A

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)


Criteria A: Delusions (1) Fixed beliefs that are not amenable to change in light of

conflicting evidence May include variety of themes:

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] ie. delusions that express loss of control over mind/body

thought withdrawal, thought insertion, delusions of control


Criteria A: Hallucinations (2)

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 Distinct from individual’s own thoughts


Criteria A: Disorganized speech (3)

Substantially impairs effective communication

Typically inferred from individual’s speech

Presentation: loose associations (switching from topic to topic tangentiality incoherence (‘word salad’)

AKA ‘formal thought disorder’


Criteria A: Disorganized behaviour 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) 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


Criteria A: Negative Symptoms

Account for substantial portion of morbidity associated w/ SZ 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)


Criteria B-F

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


Clinical manifestation

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 Commonly negative symptoms; can be severe

Mood symptoms/episodes common Assessment of these critical for making correct diagnosis


Associated features: MANYInappropriate affect

Dysphoric mood

Disturbed sleeping pattern

Lack of interest in eating

Depersonalization

Derealization

Somatic concerns

Anxiety/phobias

Cognitive deficits

Abnormal sensory processing/integrationAbnormal inhibitory capacity

Reductions in attention

Social cognition deficits

Lack of insight (anosognosia)

Deficits in executive function

Differences in cellular architecture, WM connectivity, GM volume

Reduced overall brain volume

Impairments in motor coordination

Minor physical anomalies


Prevalence & gender

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 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


Onset & course I

Typical onset b/w late teens and early 30s (we are not out of the woods yet!)

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


Onset & course II

Impaired cognition common; present during development, precede SZ stable cognitive impairments during adulthood

Predictors of course/outcome UNEXPLAINED Course favourable in ~20%

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


EOS: Early-onset schizophrenia Essential features are the same However, more difficult to make diagnosis

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


Risk factors

Environmental: season of birth, urban environment, (specific) minority ethnic groups

Genetic/physiological: strong contribution for genetic factors 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 However, vast majority of those w/ these risk factors do not develop

SZ


A note on culture

Important to consider the effect of culture, esp when individual & clinician do not share the same background

Why might this be?


Functional consequences

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 Educational progress & maintaining employment frequently

impaired Employed at lower level than parents, may not marry or have

limited social contact


Differential I 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


Differential II 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


Comorbidity

Substance-abuse disorders: high Over half use tobacco

Anxiety disorders (OCD, panic disorder) Life expectancy = reduced associated medical

conditions 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


Video!

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)

https://www.youtube.com/watch?v=bWaFqw8XnpA

http://www.wimp.com/schizophrenicsymptoms/

http://www.wimp.com/schizophrenicsymptoms/


Model: DSM-VGenetic/physiological risk factors• genes• birth complications

Environmental risk factors

Core features• Criteria A• cognitive,

behavioural, emotional dysfunctions

Gender• age of

onset

Culture

Comorbidity• substance abuse (tobacco)• anxiety• medical issues (CV, weight

gain, chronic disease, lifestyle, etc)

Functional consequences• sig social &

occupational impairment

Associated features• inappropriate affect• cognitive deficits• depersonalization• ETC


Literature


What is going to happen now:

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


Basics

First conceptualized by Emil Kraepelin as ‘dementia praecox’

Research at every level of organization: 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)


Theories

Obviously, many and varied:

Neurodevelopmental Progressive Progressive neurodevelopmental DA Glutamatergic Psychoanalytic Dysconnectivity Inflammatory


Neurodevelopmental theory 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


Genetics 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” 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*)


Cognition

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


Cognition 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)


Cognition

Rajji et al, 2009


Let’s talk about neuro

“Schizophrenia is the graveyard of neuropathologists” (Plum, 1972)

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


Neuro It all started in 1976, with a computerized tomography

study showing that pts w/ SZ have larger ventricles

Johnstone et al, 1976


Neuro

Since then, some of the most replicated findings include:

Increases in ventricular size Decrease in whole brain volume Decreases in gray matter volume Altered connectivity Altered aging Changes in neuronal density, organization, type


Ventricular size

Kempton et al, 2010


Whole brain volume

Keller et al, 2003


Gray matter

Yuksel et al, 2012


Connectivity

Skudlarski et al, 2010


Aging

van Haren et al, 2008


Neuronal changes

Solomon, 2004


EOS

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) 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


EOS


EOS 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) 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%


EOS Profile of GM loss in VEOS

(Thompson et al, 2001) 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, replicated separately in M and F


EOS Thompson et al, 2001:


EOS Neurocognition in EOS (Frangou, 2013)


EOS Neurocognition in EOS (Frangou, 2013)


EOS WM tract integrity (Kyriakopoulos et al, 2008)

n=19, mean onset=14.77, wrt HC


EOS

Brain abnormalities in EOS (Sowell et al, 2000) n=10, mean age

onset=11, age range=7-16, wrt HC

EOS=larger ventricles, changes in mid corpus callosum (WM), posterior cingulate, caudate, thalamus

Notice the difference in ventricular size


My modelGenetic/physiological risk factors• genes• birth complications

Gender• age of

onset

Core features• Criteria A• cognitive deficits• electrophysiological

diff• lack of insight

Associated features• lifestyle factors• substance abuse

(tobacco)

Comorbidity• medical issues (CV, weight

gain, chronic disease, etc)• other psych conditions

(depression)

Functional consequences• lack of job/social

skills/friends• homelessness• decreased life

expectancy (suicide)• medication side effects• poor health

Culture

Environment

Prodrome

Altered neurodevelopment

Altered gray matter, white matter, lateralization


Thank you!Questions?


References I1) Diagram slide 1: http://www.scientificamerican.com/article.cfm?id=new-genetic-model-schi2) American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders

(5th ed.). Arlington, VA: American Psychiatric Publishing.3) Diagram slide 14: http://digital-art-gallery.com/picture/111994) Weinberger, D.R. (1987). Implications of normal brain development for the pathogenesis of

schizophrenia. Arch Gen Psychiatry, 44, 660-669. 5) 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. 6) Ripke, S. (2013). Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

Nat Genet, 45, 1150-1159.7) 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.

8) 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.

9) 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.

10) Rajji, T.K., Ismail, Z., & Mulsant, B.H. (2009). Age at onset and cognition in schizophrenia: Meta- analysis. British Journal of Psychiatry, 195, 286-293.

11) Plum, F. (1972). Prospects for research on schizophrenia. 3. Neurophysiology. Neuropathological findings. Neuroscie Res Program Bull, 10, 384-388.

http://www.scientificamerican.com/article.cfm?id=new-genetic-model-schi

http://digital-art-gallery.com/picture/11199


References II12) 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, 924-926.13) 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. 14) 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.

15) 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.

16) 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.

17) 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.

18) Selemon, L.D. (2004). Increased cortical neuronal density in schizophrenia. Am J Psychiatry, 161, 9.

19) 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.

20) 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.


References III21) Röpcke, B., & Eggers, C. (2005). Early-onset schizophrenia: a 15-year follow-up. Eur Child

Adolesc Psychiatry, 14, 341-350.22) 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.

23) Frangou, S. (2013). Neurocognition in early-onset schizophrenia. Child Adolesc Psychiatr Clin N Am, 63, 519-523.

24) 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.

25) 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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Early-Onset Schizophrenia