1. Mind and brain are two sides of one coin; Disorders of the mind* are disorders of the brain. * schizophrenia, depression, anxiety, psychopathy, etc.

2. Schizophrenia Clinical features Etiology (cause) –Genetic –Environmental Neurobiology & Pharmacotherapy

3. Clinical features Positive symptoms –Hallucinations –Delusion –Disorganized Speech –Socially awkward behavior (disorganized) Negative symptoms* –Poverty of speech –flat affect, apathy, anhedonia –Decreased motor activity Cognitive symptoms* –Working memory, attention A very debilitating disease * non-specific High Dopamine Hypofrontality

4. All ethnic groups/geography Lifetime prevalence = 1% First diagnosis at 20 yrs of age Prodrome at 17 yrs of age Early detection is key, as delayed treatment: -increases brain damage, -shows less recovery Some signs present at childhood: - neuromotor functions - sociability - emotions 1020304050 years Jennen-Steinmetz et al 1997

5. Time course: - positive symptoms are evident in the acute episodes - negative symptoms increase gradually (although they can precede the positive ones, as in the prodrome) 1 st acute episode prodromerelapseresidual phase relapse

6. Schizophrenia Clinical features Etiology (cause) –Genetic: –Environmental Neurobiology & Pharmacotherapy

7. Increased risk with closer genetic distance Given that somebody is schizophrenic, what is the likelihood that you will suffer from schizophrenia? (in %) If biological parent is schizophrenic: 17% (thus schizophrenia is not due to a single gene mechanism)

8. 8 Environmental changes start in utero Identical genes ‘Same’ environment Higher concordance for schizophrenia Identical genes Slightly different environment Lower concordance for sch

9. How likely it is that your offspring will be schizophrenic? If you are schizophrenic: 17% If your fraternal twin is schizophrenic: 2% If your identical twin is schizophrenic:17% The identical twin is genetically predisposed to suffer the disease (& thus passes the genetic risk to his offspring). The identical twin is susceptible to the disease but its triggering environmental factor was absent (susceptibility hypothesis). Only 17% chance of passing schizophrenia to your offspring; - Thus, it’s not due to a single gene (unlike Huntington’s) - May be genes impart susceptibility, and other factors trigger it.

10. 10 Same story, as told by your textbook

11. -Age of father (not of mother) -Spermatocytes divide more frequently than oocytes, so increase chance of mutation (it’s not a Y chromosome mutation) -Environmental impact on a genetic factor

12. Schizophrenia Clinical features Etiology (cause) –Genetic: –Environmental Neurobiology & Pharmacotherapy

13. Environmental stress: maternal flu during pregnancy, malnourishment, obstetrics

14. Viral hypothesis (flu) Seasonal (previous slide) Urban Flu epidemic Maternal influenza during fetal development (2 nd trimester)

15. Stress hypothesis Flu is just a stressor Other stressors during 2 nd trimester also increase risk: –Underweight mother –Underweight newborn –Famine ( due to thiamine deficiency post-famine?) –Your husband is killed –Increased cortisol stress video may also explain disease onset in adolescence

16. Of those showing warning signs (prodromal phase) 1/3 gets better as they enter adulthood 1/3 continues to experience mild symptoms 1/3 develops schizophrenia or other psychosis This latter group has the higher cortisol levels at prodrome Cortisol levels increase with puberty (even in normal kids) a disruptive family environment (stressor) is a risk factor. Further evidence for cortisol hypothesis: in animal models, cortisol increase during pregnancy leads to abnormal hippocampus in the offspring

17. Obstetric complications Stress and reduction in brain oxygen during: – pregnancy –labor & delivery Evidence from animal models: –Fetal hypoxia leads to neuropathology similar to one observed in schizophrenia: Enlarged ventricles (reduced brain weight) No gliosis Most predictive for those without genetic influence

18. Abnormal brain development Pre-natal: Neuromotor oddities (e.g, posture) Minor physical abnormalities (e.g., asymmetrical ears) Post-natal: Neuromotor oddities (e.g, posture) Traumatic brain injury synaptic pruning loss of dendrites, no gliosis (i.e., scar tissue) hypofrontality small Hippocampus

19. Schizophrenia Clinical features Etiology (cause) –Genetic: –Environmental Neurobiology & Pharmacotherapy

20. 20 Neuroanatomy: - Enlarged ventricles

21. 21 -Childhood onset (13 y- old) -frontal relatively spared!

24. 24 First episode, never medicated patients AX Task AY requires inhibition BX requires working memory (retain context)

25. PCP (phenyciclidine) causes –Positive symptoms –Negative & cognitive symptoms Thus, it is a good drug for testing how schizophrenia develops PCP: –Inhibits NMDA receptors (glutamate) in frontal lobe –decreases frontal lobe activity, which in turn –causes hiperactivity in mesolimbic dopaminergic cells and –therefore triggers positive symptoms PCP: –Activates dopaminergic cells that project to n. accumbens (positive s) –Also inhibits dopaminergic cells that project to frontal lobe (negative s)

26. 26 Copyright © Allyn & Bacon 2007

27. When used chronically, PCP impairs frontal tasks (e.g., object retrieval with detour) Antipsychotic drugs: –improve performance –increase dopamine release in prefrontal cortex In sum, low DA and/or glutamate in frontal cortex can lead to high DA in VTA

28. Evidence for the role of dopamine in positive symptoms Antipsychotic drugs (D2 blockers) DA agonists (e.g., cocaine) Increased DA or increased DA receptors? PET study using amphetamines (ethics?)

29. Hypofrontality comes first: what causes it? Synaptic pruning: –Reduced dopaminergic and/or glutamatergic activity in frontal lobe Gaba: –These neurons modulate glutamatergic activity –They have to migrate longer distances in development (so more opportunities for environmental insults)

31. Pharmacotherapy Classic Dopamine blockers –Act on D2 receptors –Reduce for positive symptoms –Do not reduce negative symptoms (might increase them) –Side effects: Tardive dyskinesia due to DA receptors up regulation in basal ganglia increase hypofrontality? Atypical (2 nd generation) DA blockers –Partial agonist

32. Partial agonist: -High affinity -Low activation In frontal lobe: -Acts as agonist In n. accumbens - Acts as antagonist

33. Pharmacotherapy (cont’d) Glutamatergic drugs (clinical trials) –Glycine: It’s a NT necessary for opening NMDA channel Improves negative symptoms

34. Many unsolved mysteries… Ketamine –Similar to PCP –It is used for anesthesia in kids –Not used in adults because it can cause psychosis –Are kids’ brains unaffected, or are they more resilient? (if the latter, would we find increase schizophrenia?) Why does dopamine cause positive symptoms? –(S. Kapur)

35. … and some lessons for life Flu Vaccine Reduce maternal stress (physical & psychological) Reduce teenager’s stress Raise concern about friend/relative when you deem doing so is warranted. Support early treatment (when onset is evident)

36. Summary

37. Spare slides

39. Pre-morbid development Schizotypal personality disorder at adolescence –Social anxiety –Affective abnormalities –Eccentric behavior –Unusual ideas (e.g., persistent belief in ESP) –Unusual sensory experiences (not strong enough to be delusions or hallucinations) Relation between SPD and schizo (20-40% of SPD -> schizo), familial link

40. http://www.sfnsw.org.au/schizophrenia/sym ptoms.htm http://www.emory.edu/EMORY_MAGAZI NE/spring2000/inquiry.html