Early-Onset Schizophrenia Kirran Bakhshi Child Psychopathology November 6, 2013
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?
University of Central Florida
DSM-V
University of Central Florida
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)
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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’
University of Central Florida
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
University of Central Florida
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)
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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?
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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
University of Central Florida
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)
University of Central Florida
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
University of Central Florida
Literature
University of Central Florida
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
University of Central Florida
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)
University of Central Florida
Theories
Obviously, many and varied:
Neurodevelopmental Progressive Progressive neurodevelopmental DA Glutamatergic Psychoanalytic Dysconnectivity Inflammatory
University of Central Florida
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
University of Central Florida
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*)
University of Central Florida
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
University of Central Florida
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)
University of Central Florida
Cognition
Rajji et al, 2009
University of Central Florida
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
University of Central Florida
Neuro It all started in 1976, with a computerized tomography
study showing that pts w/ SZ have larger ventricles
Johnstone et al, 1976
University of Central Florida
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
University of Central Florida
Ventricular size
Kempton et al, 2010
University of Central Florida
Whole brain volume
Keller et al, 2003
University of Central Florida
Gray matter
Yuksel et al, 2012
University of Central Florida
Connectivity
Skudlarski et al, 2010
University of Central Florida
Aging
van Haren et al, 2008
University of Central Florida
Neuronal changes
Solomon, 2004
University of Central Florida
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
University of Central Florida
EOS
University of Central Florida
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%
University of Central Florida
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
University of Central Florida
EOS Thompson et al, 2001:
University of Central Florida
EOS Neurocognition in EOS (Frangou, 2013)
University of Central Florida
EOS Neurocognition in EOS (Frangou, 2013)
University of Central Florida
EOS WM tract integrity (Kyriakopoulos et al, 2008)
n=19, mean onset=14.77, wrt HC
University of Central Florida
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
University of Central Florida
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
University of Central Florida
Thank you!Questions?
University of Central Florida
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.
University of Central Florida
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.
University of Central Florida
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.