Early-Onset Schizophrenia

1. Early-Onset Schizophrenia Kirran Bakhshi Child Psychopathology November 6, 2013

2. 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?

3. DSM-V

4. 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)

5. 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

6. 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

7. 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’

8. 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

9. 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)

10. 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

11. 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

12. Associated features: MANY Differences in cellular architecture, WM connectivity, GM volume 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 Reduced overall brain volume Cognitive deficits Reductions in attention Minor physical anomalies Anxiety/phobias Lack of interest in eating

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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?

19. 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

20. 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

21. 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

22. 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

23. 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? TEDTalkhttp://www.wimp.com/schizophrenicsymptoms/ • Also: Jani, Dxw/ SZ at age 6 (on Oprah, Dr Phil, Discovery Health) • Many videos of Elyn Saks (TEDTalk, interviews, etc)

24. Model: DSM-V • Genetic/physiological risk factors • genes • birth complications Environmental risk factors Culture • Functional consequences • sig social & occupational impairment • Core features • Criteria A • cognitive, behavioural, emotional dysfunctions • Gender • age of onset • Associated features • inappropriate affect • cognitive deficits • depersonalization • ETC • Comorbidity • substance abuse (tobacco) • anxiety • medical issues (CV, weight gain, chronic disease, lifestyle, etc)

25. Literature

26. 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

27. 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)

28. Theories • Obviously, many and varied: • Neurodevelopmental • Progressive • Progressive neurodevelopmental • DA • Glutamatergic • Psychoanalytic • Dysconnectivity • Inflammatory

29. 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

30. 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*)

31. 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

32. 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)

33. Cognition Rajji et al, 2009

34. 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

35. Neuro • It all started in 1976, with a computerized tomography study showing that pts w/ SZ have larger ventricles Johnstone et al, 1976

36. 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

37. Ventricular size Kempton et al, 2010

38. Whole brain volume Keller et al, 2003

39. Gray matter Yuksel et al, 2012

40. Connectivity Skudlarski et al, 2010

41. Aging van Haren et al, 2008

42. Neuronal changes Solomon, 2004

43. 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

44. EOS

45. 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%

46. 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

47. EOS • Thompson et al, 2001:

48. EOS • Neurocognition in EOS (Frangou, 2013)

49. EOS • Neurocognition in EOS (Frangou, 2013)

50. EOS • WM tract integrity (Kyriakopoulos et al, 2008) • n=19, mean onset=14.77, wrt HC