Schizophrenia

1. Schizophrenia Schizophrenia

2. Case Study 1 • Mike is a 33 year old divorced white male with two children he rarely ever sees. He has a college education and has a degree in computer science. • Mike says he knows someone has removed his brain and replaced it with someone else's. He believes that this brain is controlling him and that he is not responsible for his actions. Schizophrenia

3. Case Study 1 • He works everyday and has been on his current job for 15 years. He says he has lots of friends but sometimes he thinks its one of them who did this to him. His family physician has tried to get him to see a local psychiatrist but Mike refuses to go. Schizophrenia

4. Case Study 2 • Jack, 24, graduated from high school and got a job working in a video store. After working for about 6 months Jack began to hear voices that told him he was no good. He also began to believe that his boss was planting small videocameras in the returned tapes to catch him making mistakes. Jack became increasingly agitated at work, particularly during busy times, and began talking strangely to customers. • For example one customer asked for a tape to be reserved and Jack indicated that that tape may not be available because it had “surveilance photos of him that were being reviewed by the CIA". Schizophrenia

5. Case Study 2 • After about a year Jack quit his job one night, yelling at his boss that he couldn't take the constant abuse of being watched by all the TV screens in the store and even in his own home.Jack lived with his parents at the time. He became increasingly confused and agitated. His parent took him to the hospital where he was admitted. Schizophrenia

6. Prevalence, Etiology • 1% of population for past 30 years (Thaker & Carpenter, 2001) 1. Some suggestion that the cause may be genetic (Miyamoto et al., 2003) • Heritability (twin studies) up to 90% • Number of genes have been implicated: • Dysbindin (DTNBP1): synaptic plasticity, signal transduction • Neuregulin (NRG1): neuronal migration and brain development • Series of genes related to myelination and/or oligodendrocyte function Schizophrenia

7. Prevalence, Etiology 2. Number of environmental factors • City dwellers (high population density) • Born during late winter or early spring (Feb to May) • (Higher) latitude • Maternal factors: especially inflammatory responses to infection, prenatal malnutrition, stress • Neonatal factors: Rh incompatibility, prematurity, low birthweight, complications during delivery Schizophrenia

8. Symptoms • Positive (presence is diagnostic) • Hallucinations: perceptions of stimuli that are not actually present • Thought disorders: disorganized, irrational thinking, poor logic, nonsense speech • Delusions: beliefs that are contrary to fact • persecution • grandeur • control Schizophrenia

9. Symptoms • Negative (absence of normal behaviours) • Flattened emotional response • Poverty of speech • Lack of initiative and persistence • Anhedonia (inability to experience pleasure) • Social withdrawal • These are not specific to schizophrenia Schizophrenia

10. Symptoms • Common cognitive impairments: attention, memory and executive functions (IQ subtests). • Often dramatic (two standard deviations below that of healthy controls) • Growing evidence that cognitive impairments are a distinct dimension of illness (Keefe and Hawkins, 2006) • May be apparent prior to disease onset, especially areas of executive functioning. • Sensory and motor performance deficits as well (“neurological soft signs”) Schizophrenia

11. DSM-IV Criteria A. Characteristic symptoms: Two or more of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): 1) delusions 2) hallucinations 3) disorganized speech 4) grossly disorganized or catatonic behaviour 5) negative symptoms Schizophrenia

12. DSM-IV Criteria B. Social/occupational dysfunction: One or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved prior to the onset C. Duration: Continuous signs of the disturbance persist for at least 6 months. Schizophrenia

13. DSM-IV Criteria D. Must exclude Schizoaffective or Mood Disorders E. Must exclude substance use or general medical conditions. F. If there is a history of Pervasive Developmental Disorders (PDDs), the additional diagnosis of Schizophrenia is made only if prominent delusions or hallucinations are also present for at least 1 month. Schizophrenia

14. DSM-IV Criteria Subtypes vary with primary symptoms: • Paranoid (delusions or auditory hallucinations) • Disorganized (speech or behaviour, flat affect) • Catatonic (motoric immobility/stupor or excessive/excitive motor activity) • Undifferentiated Schizophrenia

15. DSM-IV Criteria • Associated diagnoses: • Schizophreniform disorder (less severe in terms of symptoms and functioning) • Schizoaffective (mood disorder plus delusions or hallucinations) • Delusional disorder (delusions alone: erotomanic, grandiose, jealous, persecutory, somatic) • Brief psychotic disorder • Shared psychotic disorder (folie a deux) Schizophrenia

16. Neuropathology 1. Dopamine Hypothesis • Schizophrenia is caused by overactivity of dopaminergic synapses • Mesolimbic pathway: ventral tegmental area, nucleus accumbens, amygdala Schizophrenia

17. Neuropathology • Increased dopamine release (Laruelle, et al., 1996; Brieier et al., 1997) • D2 receptor hyperexcitability • DA agonists induce psychotic symptoms in healthy subjects (cocaine, amphetamine) • Increased postsynaptic response to dopamine release (Kestler, Walker, & Vega, 2001) • Presynaptic DA abnormality • Dysfunction in storage and metabolism at the axon terminal (hyper-responsiveness) • Prolonged activation of postsynaptic receptors Schizophrenia

18. Neuropathology 2. The Serotonergic Hypothesis • Serotonergic hyper-excitability can also produce hallucinations (I.e. LSD) • 5-HT 2A and 1A receptor subtypes appear to be the one of the sites of action of atypical antipsychotics • Serotonergic pathways in pre-frontal cortex may be disrupted or impaired in schizophrenics There is likely a disruption of all monoamine pathways in the mesolimbic/mesocortical pathway Schizophrenia

19. Neuropathology 3. Brain Abnormalities shown postmortem, or with CT, PET, MRI • Not related to loss of tissue, rather to disrupted developmental processes (neuron size, increased cellular packing density) • Reduction (bilateral) in the size of the hippocampus • Enlargement of the ventricles (non-specific to schizophrenia) • Reduced brain volume overall Schizophrenia

20. Neuropathology 4. A neurodevelopmental disorder? • Abnormalities of early brain development increase risk for subsequent clinical symptoms • Established correlation between developmental pathology (precursory/prodromal symptoms) and adult psychosis • Schizophrenia may degenerative, with worsening of function over time • Association between first-episode psychosis and structural brain changes Schizophrenia

21. Neuropathology 4. A neurodevelopmental disorder? • Seems to be associated with some physical dysmorphisms (Schiffman et al., 2002) • head circumference too large or small • two or more hair whorls (cowlicks) • wide-set eyes • low-set or asymmetrical ears • high palate • curved fifth finger, single crease in palm Schizophrenia

22. Neuropathology • Recent research suggests that some neural degeneration may occur in adolescents with early-onset schizophrenia • Thompson et al (2001) - loss of cortical gray matter volumne starting in parietal lobes and progressing through temporal and frontal lobes • May be related to prenatal influences being activated by pubertal hormones, or stresses associated with adolescence. Schizophrenia

23. Neuropathology 4. Different symptoms caused by separate pathways. • Positive symptoms are caused by hyperactivity of DA synapses in nucleus accumbens (Carr & Sesack, 2000). • Negative symptoms are caused by brain abnormalities, particularly loss of frontal neurons • Hypo-excitability of (dorsolateral) prefrontal cortex • Reduction of inhibition • Associated with less activation of the frontal lobes on PET (Taylor, 1996) Schizophrenia